Glycolipids for therapeutic use and pharmaceutical compositions thereof

Abstract

The present application provides glycolipids and pharmaceutical compositions thereof for therapeutic uses. Use of a compound of Formula I: R1-L1-C(A)(A’)-CH2, -L2-R2 or a pharmaceutically acceptable salt thereof for use in medicine, for example, for treating a disease or disorder selected from the group comprising: cancer, autism spectrum disorders, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, muscular atrophy, and viral infection.

Description

[0001] This application is a divisional application of Chinese Patent Application No. 201580030017.4, filed on April 7, 2015, entitled "Glycolipids for Therapeutic Use and Pharmaceutical Compositions Thereof". TECHNICAL FIELD

[0002] The present application relates to compounds suitable for use as one or more of the following: anti-proliferative agents, chemotherapeutic agents, adjuvants, and anti-viral agents and cell sensitizing agents. Preferably the compounds are inhibitors of protein translation. BACKGROUND

[0003] Disruption of one or more steps in the control of protein synthesis is associated with alterations in cell cycle and / or regulation of cell growth. Evidence supports the concept that some translation factors are proto-oncogenes and that proteins involved in the translational pathway can act as key regulators of maglinant progression (Hershey et al, 2000 Translational Control and Cancer, Cold Spring Harbor Laboratory Press, Cold Spring Harbor). Cancer cells typically show higher rates of protein synthesis compared to normal cells. Thus, deregulation of protein synthesis is emerging as a major cause of cancer progression. Over-expression of certain translation factors can lead to malignant transformation and many components of the translational pathway are over-expressed in cancer. A number of clinically relevant in vivo experiments have demonstrated that inhibition of translation can be relevant for the treatment of a range of cancer types, for example adult T-cell leukaemia, lung cancer, breast cancer and cervical cancer. The need for elevated levels of protein synthesis is a common feature of cancer cell growth; thus, it is highly likely that a broader spectrum of cancer types would also be amenable to treatment with such inhibitors.

[0004] Inhibitors of translation have demonstrated significant promise for the use of the inhibitors as adjuvants in treatment in combination with chemotherapeutic agents, such as Doxorubicin TM Rapidly proliferating tumour types, such as MCF-7 breast cancer cells, require relatively more protein synthesis than slow growing cancer cells, such as A549 lung cancer cells. These slow growing cancer cell types are more likely to be successfully treated by chemotherapeutic agents, such as Cisplatin TM) is often associated with a relatively high patient mortality. Studies have shown that cell types such as A549 lung cancer or SKOV3 ovarian cancer cells derive resistance to platinum-based therapies through the aberrant translation of specific proteins such as LARP1. Experimental evidence also indirectly suggests that endogenous inhibitors of protein synthesis such as programmed cell death 4 (PDCD4) modulate sensitivity to cisplatin TM ) and that the levels of these endogenous inhibitors are significantly correlated with disease-free survival of ovarian cancer patients.

[0005] Therapeutic modulation of protein translation by inhibition of the eIF4A RNA helicase is a proven target for treatment of a wide range of cancer types. Modulation of protein synthesis at the level of translation initiation (eIF4F complex containing eIF4A) is particularly important in cancer cell growth as they are highly metabolically active. This rapid growth places a great demand on the protein synthesis machinery. In addition, cancer cells will often produce proteins that are resistant to commonly used chemotherapeutic agents and this resistance is determined by key proteins that are dependent on eIF4A for selective translation. New or acquired resistance to platinum chemotherapy is a major cause of death in some cancers (e.g. ovarian cancer) and studies with high impact have shown that this chemoresistance is due to the aberrant translation of key proteins (e.g. Boussemart et al 2014, Nature, pre-publication doi: 10.1038 / nature 13572; Wolf et al. 2014 Nature, pre-publication doi: 10.1038 / nature 13485); see also reviews Blagden and Willis, 2011 Nature Oncology Reviews, 8:280-291; Bitterman. and Polunovsky 2012, Molecular Cancer Theraputics, 11 : 1051-1061).

[0006] Thus, therapeutic modulation of mRNA translation, inhibition of eIF4A is an excellent and well documented intervention point for the treatment of a range of different cancer types; enabling selective treatment directed at the biology of cancer cells, the initiation of translation is a convergence point for multiple aberrant signalling cascades and represents a logical approach for targeting chemoresistant cancer cells (cancer types include, but are not limited to, ovarian cancer, lung cancer, breast cancer, leukaemia, pancreatic cancer, kidney cancer).

[0007] There is now compelling evidence that abnormal control of protein synthesis is associated with the progression of a range of other conditions and diseases. Chronic conditions such as muscle atrophy (muscle wasting, muscle loss), autistic spectrum disorders, Alzheimer's disease, Huntington's disease and Parkinson's disease all share similar patterns of protein synthesis dysregulation and a number of studies have indicated that drugs targeting the protein synthesis machinery are a potential therapeutic approach to such conditions. Further experimental evidence has also indicated that translational inhibitors or compounds acting to modify or alter protein synthesis represent an attractive opportunity for broad acting antiviral agents, for example, the compound hippuristanol has been shown to be effective in disrupting the control of HIV viral translation and the indications from studies using translational inhibitors such as hippuristanol indirectly suggest that this is a relatively non-toxic therapeutic option.

[0008] It has been shown that the herpes simplex virus HSV-1 is able to stimulate eIF4E phosphorylation and eIF4F complex formation in resting primary human cells and it is also known that the VHS protein (viral host shut-off), HSV viral endonuclease binds selectively to eIF4A and eIF4H during the viral life cycle. In addition to degrading host mRNA, VHS is thought to play a role in regulating the temporal pattern of viral mRNA expression by enhancing viral RNA translation, VHS binds to eIF4A / eIF4H and despite its endonuclease activity, this binding to eIF4A has been shown to enhance translation from viral IRES (internal ribosome entry site) elements and sequences within the FISV-15'-UTR (Saffran et al, 2010. J. Virol. 84, 6041-6049; reviewed by Walsh, D. (2010). Biochem. Soc. Trans. 38, 1511-1516).

[0009] The relative expression of the two isoforms of the HIV-1 Gag protein, p55 and p40, is highly dependent on the proper functioning of the translation initiation complex with respect to the human immunodeficiency virus (HIV). The highly structured 5'-UTR of the viral p55 gene has been shown to be strictly controlled by the required eIF4F complex, in particular the RNA replicase eIF4A, for expression (de Breyne et al, 2012. FEBS J. 279, 3098-3111). Additional studies using known inhibitors of eIF4A, the polyhydric naftol, have evaluated the requirement of eIF4A in the proper translation of HIV proteins, with increasing amounts of polyhydric naftol inhibiting the translation of the three Gag isoforms in a similar dose- response manner, thereby confirming the functional requirement of eIF4A in the HIV life cycle (Looker et al. 2010, Nucleic Acids Res. 39, 2367-2377), recent work by Plank et al. (2014. Vol. 2, Iss. 1) confirmed that polyhydric naftol treated HeLa cells (transfected with HIV-1 leader constructs) inhibited IRES activity with IC50 values in the drug peak range (163 to 296 nM), these results confirm that eIF4A is important in the HIV life cycle and present an attractive new therapeutic target for this virus.

[0010] Inhibitors of eIF4A have been shown to be of value in preventing influenza virus replication (e.g., WO2013152299A2). Recent studies have shown that the functional impairment of eIF4A is associated with the inhibition of influenza virus mRNA translation and protein synthesis, and that this helicase is essential for viral translation (data from in vivo and in vitro analyses) (Yanguez et al, 2011. Virology. 413, 93-102). It has been shown that viral mRNAs do not contain cis-acting signals that can mediate eIF4A-independent translation, and it is also known that trans-acting viral proteins cannot substitute for the function of mammalian eIF4A. Thus, inhibition of eIF4A is an attractive target to stop the multiplication and replication of influenza virus in infected cells.

[0011] Coronaviruses (e.g., human coronaviruses) are believed to be responsible for up to one-third of the causes of common colds, and are also responsible for severe viral infections such as SARS. Coronavirus replication involves the production of mRNA with a capped 5' UTR. Coronavirus 5' UTRs, e.g., those identified from SARS isolates, are relatively very conserved, and the track sequence forms a complex secondary structure containing four stem-loop domains. Since the requirement for eIF4A by the 5' UTR secondary structure is directly related, it is not surprising that eIF4A is considered a therapeutic target for coronavirus infection.

[0012] Translation of most coronavirus mRNAs is believed to be cap-dependent and requires the functional translation initiation complex eukaryotic initiation factor 4F (eIF4F) (Cencic et al, 2011. J Virol. 85, 6381-6389). Inhibition of translation with the eIF4A inhibitors pateamine A or silvestrol causes a 10- to 100-fold reduction in the titers of infectious coronavirus released by infected cells (Cencic et al, 2011 J Virol. 85, 6381-6389). This virus has been shown to be dependent on eIF4A and a significant reduction in viral progeny was observed once eIF4A was inhibited (Cencic et al, 2011. Virol 85, 6381-6389).

[0013] Rhinoviruses are the most common viral infective agent of humans and are the major cause of the common cold. The internal ribosome entry site element of poliovirus (PV), human rhinovirus (HRV) and encephalomyocarditis virus (EMCV), foot-and-mouth disease virus (FMDV) groups are inhibited by disruptive mutations in the eIF4A protein (Svitkin et al, 2001. RNA. 7, 382-394). Thus, these viruses are dependent on eIF4A activity.

[0014] HCMV (Human Cytomegalovirus) is a herpes virus with serious and life-threatening consequences for immunocompromised patients. As HCMV infection progresses, the abundance of the core eIF4F assembly (eIF4A is part of the eIF4F complex) increases greatly (Walsh et al, 2005. J. Virol. 19, 8057-8064). Moreover, HCMV UL69, which is homologous to the HSV-1 ICP27 protein, binds to eIF4A (Aoyagi et al, 2010. Proc. Natl Acad. Sci. U.S.A. 107, 2640-2645). Pateamine A, a known inhibitor of eIF4A, inhibits the replication of HCMV (see patent WO 2013152299 A2). Disruption of eIF4A activity offers a therapeutic target as an antiviral against HCMV.

[0015] There is good evidence that the translation initiation of Norovirus proteins is dependent on the interaction of the VPg with the translation initiation complex (Daughenbaugh et al, 2003. EMBO J. 11, 2852-2859; Daughenbaugh et al, 2006. Virol J. 23, 3-33). Pateamine A has been shown to be an inhibitor of eIF4A, with the potential to interfere with the VPg / eIF4F complex, as it disrupts the helicase activity / NTPase activity of eIF4A, rendering it dysfunctional in the eIF4F complex (Bordeleau et al, 2006. Chem Biol. 13, 1287-1295). Therefore, virologists have suggested that inhibitors of eIF4A could be exploited as antivirals against Norovirus (see Rocha-Pereira and Nascimento, 2012 Targeting Norovirus: Strategies for the Discovery of New Antiviral Drugs, Antiviral Drugs - Aspects of Clinical Use and Recent Advances, Dr. Patrick Arbuthnot (F.d.), ISBN: 978-953-51-0256-4, InTech).

[0016] Recent high-impact studies on the causes of ASD have identified dysregulation of protein synthesis at the initiation of translation in neuronal cells as a major inducer of ASD symptoms (Gkogkas et al, 2013 Nature, 2013, 493:371-377; Santini et al, Nature, 2013, 493:411-415).

[0017] Work by the Sonenberg lab (Gkogkas et al 2013. Nature, 493, 371-377) demonstrated a direct link between ASD and the relative translation of two proteins in neurons; these are the proteins that mediate the formation of new connections between neuronal cells and regulate neurotransmitter receptors. This new study showed that the ratio of synthesis of these two proteins is selectively determined by the activity of the translation initiation complex, and that dysregulation of synthesis drives or contributes to the symptoms of ASD. Importantly, it is the relative synthesis of the neuroligins 1 (NLGN1) protein that is dysregulated; thus, selective control of NLGN1 has been shown to be a viable therapeutic option for ASD.

[0018] In the model of Gkogkas et al (2013. Nature, 493, 371-377), therapeutic intervention to regulate NLGN1 is mediated via inhibition of eIF4E, a key protein in the translation initiation complex. However, the helicase eIF4A represents an additional and more selective new target for control of NLGN1 synthesis (a target that elevates ASD symptoms). The function of the eIF4A helicase is to unwind long and complex structured 5'UTRs; this is necessary before protein synthesis can begin. Inhibition of eIF4A selectively reduces the synthesis of proteins with larger 5'UTR secondary structures or longer length, while not inhibiting those with short 5'UTRs or unstructured UTRs. Treatment of cells with a coral-derived inhibitor of eIF4A, polyoxin, results in selective inhibition determined by the features present in the 5'UTR (e.g. Bottley et al, 2010 PLOS One, 5(9):e13030).

[0019] While the need for chemical modifiers of protein translation is well established, most current small molecule inhibitors, such as polyoxin, are derived from rare marine corals or sponges and prove difficult to synthesize in any meaningful quantity. However, these molecules have been successfully used to provide in vivo evidence that such inhibitors can be suitable for diagnostic use, however these molecules are limited in their source and thus not a viable option for clinical use. SUMMARY

[0020] It is an object of the present invention to provide new protein translation inhibitors, such as inhibitors of eukaryotic ribosomal activity, which can be used as anti-proliferative agents, chemotherapeutic agents, anti-viral agents, cytosenitizers and / or adjuvants. Inhibitors of eukaryotic ribosomal activity can selectively inhibit eIF4A-dependent or independent translation initiation.

[0021] The present invention can provide, inter alia, compounds for use as anti-proliferative, chemotherapeutic, anti-viral, cytosenitizing or adjuvant agents, and pharmaceutical compositions comprising said compounds. The compounds can be used in the treatment of diseases and disorders associated with cell proliferation, such as cancer, or in the treatment of diseases and disorders associated with abnormal control of protein synthesis, such as cancer, viral infection, muscle atrophy, autism spectrum disorder, Alzheimer's disease, Huntington's disease and Parkinson's disease.

[0022] The present invention provides, according to a first aspect, a compound of formula I:

[0023] Rl-Ll-C(A)(A’)-CH2-L2-R2(I)

[0024] or a pharmaceutically acceptable salt thereof,

[0025] wherein:

[0026] Rl is selected from a carbohydrate group or derivative thereof, hydrogen, a C1-C24 alkyl group or C1-C24 derivative of an alkyl group, a C2-C24 alkenyl group or C2-C24 derivative of an alkenyl group, and a C2-C24 alkynyl group or C2-C24 derivative of an alkynyl group;

[0027] L1 is a linking group;

[0028] L2 is a linking group;

[0029] R2 is selected from hydrogen, a C1-C24 alkyl group or C1-C24 derivative of an alkyl group, a C2-C24 alkenyl group or C2-C24 derivative of an alkenyl group, and a C2-C24 alkynyl group or C2-C24 derivative of an alkynyl group;

[0030] A is selected from hydrogen and a C1-C6 alkyl group;

[0031] A’ is selected from hydrogen, a C1-C6 alkyl group, and L3-3;

[0032] wherein

[0033] L3 is a linking group; and

[0034] R3is selected from the group consisting of hydrogen, a Ci-C24alkyl group or a Ci-C24derivative of an alkyl group, a C2-C24alkenyl group or a C2-C24derivative of an alkenyl group, and a C2-C24alkynyl group or a C2-C24derivative of an alkynyl group;

[0035] and wherein if A' is not L3-R3, then R2is a C10-C24alkyl group or a C10-C24derivative of an alkyl group, a C10-C24alkenyl group or a C10-C24derivative of an alkenyl group, or a C10-C24alkynyl group or a C10-C24derivative of an alkynyl group.

[0036] and wherein if A' is L3-R3, then one or both of R2and R3is a C10-C24alkyl group or a C10-C24derivative of an alkyl group, a C10-C24alkenyl group or a C10-C24derivative of an alkenyl group, or a C10-C24alkynyl group or a C10-C24derivative of an alkynyl group. BRIEF DESCRIPTION OF DRAWINGS

[0037] Embodiments of the present application will now be described, by way of example only, with reference to the accompanying drawings in which:

[0038] Figure 1 - shows the specific chemical structure of a compound of formula II as an example of a compound I of formulae I and la.

[0039] Figure 2 - shows that compounds of formula II inhibit translation and protein synthesis. Established techniques such as polyosome profiling were used to show a decrease in the number of polysomes in neuroblastoma cells after treatment with a compound of formula II. The increasing number of ribosomes associated with mRNA is shown from left to right by the polysome peaks. This is indicated by the peak at 3 ribosomes after treatment with a compound of formula II, showing that translation is rapidly and reproducibly perturbed. Cells were treated with a compound of formula II for 20 minutes, then harvested and prepared as described in Materials and Methods. The supernatant was loaded onto a 10% to 50% sucrose gradient and spun for 2 hours at 38,000 rpm. The gradient was visualised using a UV detector. A decrease in the content of polysomes was observed after treatment with a compound of formula II.

[0040] Figure 3a- shows that treatment of SH-SY5Y cells with the compound of Formula II (referred to as "active") results in selective inhibition of the amyloid precursor protein APP 5'UTR luciferase reporter relative to the Renilla luciferase reporter construct containing a short unstructured 5'UTR. SH-SY5Y cells were co-transfected with the APP-5'UTR luciferase construct and the Renilla control vector simultaneously. Luciferase levels were assayed using a Glomax luminometer and Stop-n-Glo luciferase reagent (Promega) using standard procedures. Data presented represent 8 biological replicates and the active semi-purified compound of Formula II was used as the active agent. Compound levels were estimated based on the amount of pure compound obtained from fresh tomato tissue.

[0041] Figure 3b - shows experimental results where neuroblastoma cells were transfected with a firefly luciferase translation reporter 24h prior to treatment, and then cells were treated with the compound of Formula II (active) or 1 μΜ polyhydroxynated naphthalene for 4h. The graph represents 4 biological replicates for each treatment, and 2 separate treatments of the compound of Formula II. Translation reporter activity was equivalent to both experiments treated individually with 1 μΜ polyhydroxynated naphthalene (inhibitor of eIf4A) alone.

[0042] Figure 3c - shows experimental results where cells were transfected with a firefly luciferase translation reporter 24h prior to treatment, and then cells were treated with polyhydroxynated naphthalene (1 μΜ) or polyhydroxynated naphthalene + compound of Formula II (active) for 4h. The graph represents 4 biological replicates for each treatment. Polyhydroxynated naphthalene and polyhydroxynated naphthalene + compound of Formula II resulted in significant inhibition (p = 0.01 and 0.009, respectively). No difference was observed between polyhydroxynated naphthalene and polyhydroxynated naphthalene + compound of Formula II.

[0043] Figure 3d- shows that treatment with the compound of Formula II (referred to as "the active agent") selectively reduces the level of firefly luciferase reporter gene activity that is dependent on the 5'UTR sequence. The 5'UTR of genes that are negatively associated with Alzheimer's disease progression - amyloid precursor protein (APP) and beta secretase (BACE) are inhibited by treatment with the compound of Formula II, while the equivalent reporter gene levels of the housekeeping genes, actin and thioredoxin (TXN) are not inhibited. The 5'UTR of the cancer-associated epidermal growth factor receptor (EGFR) is also selectively inhibited by treatment with the compound of Formula II. The neuroblastoma cells were transfected for 24h prior to treatment with the compound of Formula II. Following treatment, the cells were prepared as described in the Materials and Methods. Each experiment represents 6 to 8 biological replicates.

[0044] Figure 4a - shows the results of an experiment in which rapidly growing breast cancer cells MCF7 were treated with the compound of Formula II only for 96 hours. The growth of the MCF7 cell line was slowed by treatment with the compound of Formula II. The experiment represents 6 biological replicates, error = S.E.M.

[0045] Figure 4b - shows the results of an experiment in which rapidly growing breast cancer cells MDA-MB-231 were treated with the compound of Formula II only for 96 hours. The growth of the MDA-MB-231 cell line was slowed by treatment with the compound of Formula II. The experiment represents 6 biological replicates, error = standard error (S.E.M).

[0046] Figure 4c - shows the results of an experiment in which slowly growing SKOV3 ovarian cancer cells were treated with the compound of Formula II only for 96 hours. The growth of the SKOV3 cell line was slowed by treatment with the compound of Formula II at a higher dose. The experiment represents 6 biological replicates, error = standard error.

[0047] Figure 4d - shows the results of an experiment in which slowly growing A549 lung cancer cells were treated with the compound of Formula II + very low dose of Cisplatin (1 μΜ) for 96 hours. Cisplatin-resistant A549 lung cancer cells were sensitized to treatment with the compound of Formula II in combination with 1 μΜ Cisplatin - complete killing was achieved with a higher dose of the compound of Formula II. TM

[0048] Figure 4e ​- Results from an experiment in which slowly growing SH-SY5Y neuroblastoma cancer cells were treated with Compound of Formula II + low dose cisplatin for 96 hours are shown. Cisplatin resistant A549 lung cancer cells were sensitized to treatment with Compound of Formula II in combination with 2.5 μΜ cisplatin - complete killing was achieved with higher doses (10 μg) of Compound of Formula II.

[0049] Figure 4f - Results from an experiment in which slowly growing SKOV-3 ovarian cancer cancer cells were treated with Compound of Formula II + low dose cisplatin for 96 hours are shown. Cisplatin resistant SKOV-3 ovarian cancer cancer cells were sensitized to treatment with Compound of Formula II in combination with 2.5 μΜ cisplatin (p = 0.003) (right hand bar graph in figure), while no effect was observed with equivalent levels of Compound of Formula II (left hand bar graph in figure) or cisplatin alone.

[0050] Figure 5 - Compound of Formula II (active agent) selectively inhibits translation of a gene known to exacerbate symptoms of Pervasive Developmental Disorder. Experiments performed using a published luciferase reporter system (Gkogkas et al Nature 2013, 493:371-7) demonstrate that treatment with Compound of Formula II selectively reduces translation of the longer more structured 5' untranslated region of the gene neuroligin 1 (reporter 1) relative to neuroligin 2. Selective inhibition of neuroligin 1 protein levels has been demonstrated to restore normal excitation / inhibition ratios and correct social behavior deficits observed in a mouse model of autism (see, Gkogkas et al, Nature 2013, 493:371-7). The mechanism of action and level of activity of Compound of Formula II is consistent with and comparable to a well-established translation inhibitor extracted from a rare species of coral (Pyrularia pubera - a well-established eIF4A inhibitor). In this experiment, 1 μΜ of Pyrularia pubera and 1.3 μΜ of Compound of Formula II were used.

[0051] Figure 6 - Treatment with Compound of Formula II (active agent) inhibits growth of the chemoresistant lung cancer cell line A549. Cells were treated with a range of doses of active agent for 48 or 96 hours. Each data point represents at least 4 biological replicates. Data are reproducible in different media for A549 cells in two different laboratories at Nottingham (a) Biosciences and (b) Cancer Biology and efficacy has been confirmed using standard techniques such as, WST-1 (a) and MTT (b) and stably transfected luciferase cells (not shown).

[0052] Figure 7 - shows that treatment with low doses of the compound of Formula II (active agent) sensitizes chemoresistant A549 lung cancer cells to very low levels of cisplatin (2 μΜ). Cells were treated with either 2 μΜ cisplatin alone, c. 1 μg of active substance alone or c. 1 μg of active compound in combination with 2 μΜ cisplatin. WST-1 cell proliferation assay was performed 96 hours after treatment. Experiments represent 4 independent biological replicates. A significant increase in efficacy of cisplatin was observed when treated in combination with the compound of Formula II.

[0053] Figure 8 - shows the effect of the compound of Formula II (which is an example of Formulae I and la) on chemoresistant primary canine histiosarcoma tumor cells from a 7 year old retriever biopsy. Cells were treated with a single dose of cisplatin (10 μΜ) or cisplatin + the compound of Formula II (active agent) combination for 6 days, images were taken after 6 days of treatment and represent three independent treatment wells. Each image (40x magnification) represents a large portion of the well area and is an image of the equivalent area in each photograph. Similar results were observed using the active agent combination with carboplatin (2 μΜ dose).

[0054] Figure 9a - shows the effect of treatment of A549 lung cancer cells with the synthetic molecule of Formula II. The data shown demonstrate that cell growth was inhibited by Formula II in a dose dependent manner. WST-1 cell proliferation assay was performed 72 hours after treatment. Experiments represent 4 independent biological replicates.

[0055] Figure 9b - shows that treatment of chemoresistant A549 lung cancer cells with the synthetic molecule of Formula II sensitizes the cells to very low levels of cisplatin (2 μΜ). Cells were treated with either 2 μΜ or 10 μΜ cisplatin alone or 10 μg of the synthetic molecule of Formula II in combination with 2 μΜ cisplatin. WST-1 cell proliferation assay was performed 72 hours after treatment. Experiments represent 4 independent biological replicates. A 5-fold increase in efficacy of cisplatin was observed when treated in combination with synthetic Formula II.

[0056] Figure 9c- shows that treatment of chemoresistant A549 lung cancer cells with the acetyl derivative synthesized with Formula II sensitizes the cells to very low levels of cisplatin (2 μΜ). Cells were treated with 2 μΜ, 5 μΜ or 10 μΜ of cisplatin alone, 50 μg of the synthesized acetyl derivative molecule or 30 μg of the combination of 2 μΜ cisplatin. WST-1 cell proliferation assay was performed 72 hours after treatment. The experiment represents four independent biological replicates. No effect was detected after treatment with 50 μg of the synthesized acetyl derivative, however, an 8-fold increase in efficacy of cisplatin was observed when treated with 30 μg of the synthesized acetyl derivative in combination with 2 μΜ of cisplatin.

[0057] Figure 10 - Compound 46, NLGN translation reporter assay. Figure 10 shows that the compound of Formula 46 selectively inhibits the translation of a gene known to exacerbate symptoms of autism spectrum disorder. Experiments performed using a published luciferase reporter system (Gkogkas et al 2013. Nature, 493:371-7) demonstrate that treatment with the compound of Formula II selectively reduces translation of a construct containing the 5' untranslated region of the gene neuroligin 1 (reporter 1) relative to neuroligin 2. Selective inhibition of neuroligin 1 protein levels has been shown to restore normal activation / inhibition ratios and correct social behavior deficits observed in mouse models of autism (see, Gkogkas et al, Nature 2013, 493:371-7). Figure 10 shows that the inhibitory effect on translation at this dose for this length of time is not related to the anti-proliferative activity of the molecule.

[0058] Figure 11 - natural molecule + cisplatin vs polyhydroxynonyl alcohol + cisplatin. Figure 11 shows that treatment of chemoresistant A549 lung cancer cells with the synthetic molecule of Formula II or a known inhibitor of eIF4A is both anti-proliferative. The sensitizing effect of Formula II to very low levels of cisplatin (2 μΜ) when used in combination is equivalent to polyhydroxynonyl alcohol. The ratio between anti-proliferative activity and chemosensitizing activity is also equivalent.

[0059] Figure 12 - CrPV test - natural molecule targets eIF4A. Treatment with 20 μΜ of the synthesized natural molecule selectively inhibits cap-dependent translation. Treatment with Formula II selectively reduces translation of the firefly luciferase gene relative to the Renilla gene, which is downstream of the eIF4A-independent CrPV IRES.

[0060] Figure 13- Dose curve of compounds 46, 99 and 123. Figure 13 It is shown that treatment with synthetic derivatives of the compound of formula II (46, 99 and 123) inhibits the growth of the chemoresistant lung cancer cell line A549 in a dose dependent manner. Each data point represents at least 4 biological replicates, error = standard error).

[0061] Figure 14 - Cisplatin 1 M combination experiment - compounds 46, 99 and 123. Figure 14 It is shown that treatment with synthetic derivatives of the compound of formula II (46, 99 and 123) sensitizes the chemoresistant lung cancer cell line A549 to low doses of cisplatin. Cells were treated for 96 hours with a range of doses of the active compounds in combination with a range of doses of cisplatin. Each data point represents at least 4 biological replicates, error = standard error).

[0062] Figure 15 - Structures of compounds 46, 99 and 123 are shown.

[0063] Figure 16 - It is shown that a range of synthetic derivatives of the compounds of formulae I and Ia have structure related anti-proliferative and chemosensitizing sensitizing effects. Cells were treated with a range of different derivatives at three different active compound doses (20 μM, 40 μM, 80 μM). Further experiments were also performed in combination with 2 μM cisplatin for 96 hours to determine sensitizing effects. Each data point represents at least 4 biological replicates, error = standard error).

[0064] Figure 17 - It is shown that a range of synthetic derivatives of the compounds of formulae I and Ia have structure related anti-proliferative and chemosensitizing sensitizing effects which are additive or synergistic effects for cisplatin. Cells were treated with a range of different derivatives at three different active compound doses (20 μM, 40 μM, 80 μM). Further experiments were also performed in combination with 2 μM cisplatin for 96 hours to determine sensitizing effects. Each data point represents at least 4 biological replicates, error = standard error). DETAILED DESCRIPTION

[0065] In one embodiment, the compound of formula I is not:

[0066]

[0067] In general, in embodiments where A' is L3-R3, it can be preferred that the L3 linking group is not attached to the carbon atom to which it is attached via an O group. Thus, although the L3 group can optionally contain one O group, in one embodiment this is not the group directly attached to the carbon atom to which the L3 group is attached in formula I.

[0068] For example, it can be preferred that the L3 linking group is not attached to the carbon atom to which it is attached via a heteroatom. Rather, it can be preferred that there is a C-C bond acting to link the L3 linking group to the carbon atom in formula I (to which the C-C bond is attached).

[0069] In one embodiment, L3is a linking group selected from:

[0070] (i) a C1-C6 alkylene linking group, for example, a C1-C5 alkylene linking group such as methylene or ethylene;

[0071] (ii) an ether linking group -(CH2) p O(CH2) q wherein p and q independently represent an integer from 1 to 3 and p+q is equal to 4 or less;

[0072] (iii) a C2-C4 alkenylene linking group such as vinylene;

[0073] (iv) an ester linking group -(CH2) p C(=O)O(CH2) q wherein p and q each independently represent an integer from 0 to 3 and p+q is equal to 4 or less; or an ester linking group -(CH2) p OC(=O)(CH2) q wherein p represents an integer from 1 to 3, q represents an integer from 0 to 3 and p+q is equal to 4 or less; or an amido linking group -(CH2) p C(=O)NRz(CH2) q wherein p and q independently represent an integer from 0 to 3 and p+q is equal to 4 or less, and Rz is H or C1-C4 alkyl; or an amido linking group -(CH2) p NRzC(=O)(CH2) q wherein p represents an integer from 1 to 3, q represents an integer from 0 to 3 and p+q is equal to 4 or less and Rz is H or C1-C4 alkyl;

[0074] (v) an amine linker of formula -RxN(Rz)Ry-, e.g. wherein Rxand Ryare C1-C4 alkylene, e.g. C1 or C2 alkylene, and Rzis H or C1-C4 alkyl, e.g. C1 or C2 alkyl;

[0075] (vi) a thioether linker -(CH2) p S(CH2) q - wherein p represents an integer from 1 to 3 and q represents an integer from 0 to 3 and p+q is equal to 4 or less.

[0076] In one embodiment, L3is a linker selected from the following groups:

[0077] (i) a C1-C4 alkylene linker such as methylene or ethylene;

[0078] (ii) an ether linker -(CH2) p O(CH2) q - wherein p and q independently represent an integer from 1 to 3 and p+q is equal to 4 or less;

[0079] (iii) a C2-C4 alkenylene linker such as ethenylene;

[0080] (iv) an ester linker -(CH2) p C(=O)O(CH2) q - wherein p and q each independently represent an integer from 0 to 3 and p+q is equal to 4 or less; or an ester linker -(CH2) p OC(=O)(CH2) q - wherein p represents an integer from 1 to 3 and q represents an integer from 0 to 3 and p+q is equal to 4 or less; or an amido linker -(CH2) p NRzC(=O)(CH2) q - wherein p and q independently represent an integer from 0 to 3 and p+q is equal to 4 or less, and Rzis H or C1-C3 alkyl; or an amido linker -(CH2) p NRzC(=O)(CH2) q - wherein p represents an integer from 1 to 3 and q represents an integer from 0 to 3 and p+q is equal to 4 or less, and Rzis H or C1-C3 alkyl;

[0081] (v) an amine linker of formula -RxN(Rz)Ry-, e.g. wherein Rxand Ryare C1-C4 alkylene, e.g. C1 or C2 alkylene, and Rzis H or C1-C4 alkyl, e.g. C1 or C2 alkyl;

[0082] (vi) a thioether linker -(CH2) pS(CH2) q - wherein p and q independently represent an integer from 1 to 3, and p+q is equal to 4 or less.

[0083] In some embodiments, no asymmetric carbon atom (no chiral center) is present in the compound in the moiety -C(A)(A')-CH2-L2-R2. However, an asymmetric carbon atom (chiral center) can be present in the Rl-Ll- moiety of the compound, in particular when this is a sugar group, an asymmetric carbon atom (chiral center) can be present in Rl.

[0084] In the embodiments wherein A' is L3-R3, it can be preferred that -L3-R3 is equivalent to -CH2-L2-R2.

[0085] In one embodiment, A' is L3-R3, and R2 and R3 are both C10-C24 alkyl or C10-C24 derivative of an alkyl group, C10-C24 alkenyl or C10-C24 derivative of an alkenyl group, or C10-C24 alkynyl group or C10-C24 derivative of an alkynyl group.

[0086] In the embodiments wherein A' is not L3-R3, it can be preferred that A and A' are identical.

[0087] In one embodiment, A' is not L3-R3, and A and A' are both identical C1-C6 alkyl groups, for example, both methyl, or both ethyl, or both n-propyl.

[0088] For the compounds wherein no asymmetric carbon atom (no chiral center) is present in the compound in the moiety -C(A)(A')-CH2-L2-R2, the compounds can have improved solubility properties, thereby enabling the compounds to be more readily acted upon and more readily formulated into pharmaceutical compositions.

[0089] It is preferred that Rl is not hydrogen. It is more preferred that Rl is a sugar group or a derivative thereof, in one embodiment, the Rl comprises a sugar group, and the sugar is selected from the group consisting of galactose, glucose and mannose and derivatives thereof.

[0090] In one embodiment, the compound does not comprise a glycosidic linker. This can result in a product that degrades more slowly, as it does not have an anomeric position that can be easily cleaved. A product that is more difficult to enzymatically degrade will be more stable. The options for the linker group Ll are shown below, and it can be seen that these include linking groups, such as alkylene groups, thus not glycosides.

[0091] In the compounds of Formula I, it is preferred that one or more C=C double bonds, such as two or more C=C double bonds, or three or more C=C double bonds, are contained within the -C(A)(A')-CH2-L2-R2moiety of the compound. For example, there can be from 1 to 8 C=C double bonds, such as from 2 to 8 C=C double bonds, or from 2 to 6 C=C double bonds.

[0092] In one embodiment, the R2group contains one or two or three (or more) C=C double bonds.

[0093] In one embodiment, the A' group and the R2group both contain one or more C=C double bonds, for example, this can be that the A' group and the R2group both independently contain one or two or three (or more) C=C double bonds.

[0094] It is preferred that the (or each) C=C double bond contained within the -C(A)(A')-CH2-L2-R2moiety of the compound is located more than 6 atoms up the chain from the L1group but less than 17 atoms up the chain from the L1group, such as more than 6 atoms up the chain from the L1group but less than 16 atoms up the chain from the L1group, for example, more than 6 atoms up the chain from the L1group but less than 15 atoms up the chain from the L1group (or more than 6 but less than 14 atoms).

[0095] It is preferred that one or more C=C double bonds are present which are located more than 6 atoms up the chain from the L1group but less than 17 atoms up the chain from the L1group, such as more than 6 atoms up the chain from the L1group but less than 16 atoms up the chain from the L1group, for example, more than 6 atoms up the chain from the L1group but less than 15 atoms up the chain from the L1group (or more than 6 but less than 14 atoms).

[0096] It is possible that two or more C=C double bonds are present which are located more than 6 atoms up the chain from the L1group but less than 17 atoms up the chain from the L1group, such as more than 6 atoms up the chain from the L1group but less than 16 atoms up the chain from the L1group, for example, more than 6 atoms up the chain from the L1group but less than 15 atoms up the chain from the L1group (or more than 6 but less than 14 atoms).

[0097] It is possible that two or more C=C double bonds are present which are located more than 8 atoms up the chain from the L1group but less than 17 atoms up the chain from the L1group, such as more than 9 atoms up the chain from the L1group but less than 17 atoms up the chain from the L1group, for example, more than 10 atoms up the chain from the L1group but less than 17 atoms up the chain from the L1group (or more than 11 but less than 17 atoms).

[0098] In one embodiment, both the A' group and the R2group contain one or more C=C double bonds located more than 6 atoms but less than 17 atoms from the L1group along the chain, e.g., the A' group can contain one or two (or more) C=C double bonds located more than 6 atoms but less than 17 atoms from the L1group along the chain, and the R2group can contain one or two (or more) C=C double bonds located more than 6 atoms but less than 17 atoms from the L1group along the chain. In one embodiment, the A' group can contain one or two (or more) C=C double bonds located more than 7 atoms but less than 17 atoms from the L1group along the chain and the R2group contains one or two (or more) C=C double bonds located more than 7 atoms but less than 17 atoms from the L1group along the chain. In one embodiment, the A' group can contain one or two (or more) C=C double bonds located more than 10 atoms but less than 17 atoms from the L1group along the chain and the R2group can contain one or two (or more) C=C double bonds located more than 10 atoms but less than 17 atoms from the L1group along the chain.

[0099] Optionally, there can be one or more C=C double bonds located more than 13 atoms from the L1group along the chain, such as more than 14 atoms, e.g., more than 15 atoms, or more than 16 atoms, or more than 17 atoms from the L1group along the chain.

[0100] Possibly optionally, there can be two or more C=C double bonds located more than 13 atoms from the L1group along the chain, such as more than 14 atoms, e.g., more than 15 atoms, or more than 16 atoms, or more than 17 atoms from the L1group along the chain.

[0101] In one embodiment, both the A' group and the R2group contain one or more C=C double bonds located more than 13 atoms from the L1group along the chain, e.g., the A' group can contain one or two (or more) C=C double bonds located more than 13 atoms (or more than 14 atoms) from the L1group along the chain, and the R2group can contain one or two (or more) C=C double bonds located more than 13 atoms (or more than 14 atoms) from the L1group along the chain.

[0102] In one embodiment, both the A' group and the R2group contain one or more C=C double bonds, e.g., the A' group can contain 1 to 3 (or more) C=C double bonds, and the R2group can contain 1 to 3 (or more) C=C double bonds.

[0103] In one embodiment, A is not hydrogen, A' is not hydrogen. This can result in a more hindered and thus more stable product. This is especially true when L2 is an ester linkage, allowing the ester to be viewed as an ester derived from a tertiary alcohol, which can result in a more hindered and more difficult to enzymatically cleave product, and thus more stable.

[0104] If A' is not L3-3, it can be preferred in one embodiment that R2 is a group containing one or more C=C double bonds, such as two or more C=C double bonds, or three or more C=C double bonds. For example, it is possible that R2 is a C10-C24 derivative of an alkyl group, wherein the alkyl group is substituted with one or more substituent groups and wherein the one or more substituent groups between them contain one or more C=C double bonds, such as two or more C=C double bonds, or three or more C=C double bonds. Alternatively it is possible that R2 is a C10-C24 alkenyl group, which will of course contain one or more C=C double bonds, and can contain two or more C=C double bonds or three or more C=C double bonds, alternatively it is possible that R2 is a C10-C24 derivative of an alkenyl group; the alkenyl group will of course contain one or more C=C double bonds, and can contain two or more C=C double bonds or three or more C=C double bonds, and the alkenyl group can optionally be substituted with one or more substituent groups between them containing one or more C=C double bonds.

[0105] In the embodiment wherein A' is L3-R3, it is then preferred that one or both of R2 and R3 is a group containing one or more C=C double bonds, such as two or more C=C double bonds, or three or more C=C double bonds. R2 and / or R3 can be a C10-C24 derivative of an alkyl group, wherein the alkyl group is substituted with one or more substituent groups and wherein the one or more substituent groups between them contain one or more C=C double bonds, such as two or more C=C double bonds, or three or more C=C double bonds. R2 and / or R3 can be a C10-C24 alkenyl group, which will of course contain one or more C=C double bonds, and can contain two or more C=C double bonds or three or more C=C double bonds. R2 and / or R3 can be a C10-C24 derivative of an alkenyl group; the alkenyl group will of course contain one or more C=C double bonds, and can contain two or more C=C double bonds or three or more C=C double bonds, and the alkenyl group can optionally be substituted with one or more substituent groups between them containing one or more C=C double bonds.

[0106] It is possible that R2and R3each contain one or more C= double bonds, such as two or more C=C double bonds or three or more C=C double bonds. R2and R3may be the same or can be different, and as such there does not necessarily exist an even number of C=C double bonds.

[0107] In some preferred embodiments, two or more (e.g., three or more) of the following apply:

[0108] a) Rl is a saccharide group or a derivative thereof;

[0109] b) the compound does not include a glycosidic linkage;

[0110] c) two or more C=C double bonds are contained in the -C(A)(A')-CH2-L2-R2 portion of the compound;

[0111] d) no asymmetric carbon atoms exist in the compound in the portion -C(A)(A')-CH2-L2-R2.

[0112] In some preferred embodiments, two or more (e.g., three or more) of the following apply:

[0113] a) Rl is a saccharide group or a derivative thereof;

[0114] b) the compound does not include a glycosidic linkage;

[0115] c) two or more C=C double bonds are contained in the -C(A)(A')-CH2-L2-R2 portion of the compound, and one or more C=C double bonds are located on the chain more than 6 atoms but less than 17 atoms from the L1group;

[0116] d) no asymmetric carbon atoms exist in the compound in the portion -C(A)(A')-CH2-L2-R2.

[0117] In some preferred embodiments, two or more (e.g., three or more) of the following apply:

[0118] a) Rl is a saccharide group or a derivative thereof, wherein Rl contains a saccharide group and the saccharide is selected from the group consisting of galactose, glucose, and mannose, and derivatives thereof;

[0119] b) the compound does not include a glycosidic linkage;

[0120] c) two or more C=C double bonds are contained in the -C(A)(A')-CH2-L2-R2 portion of the compound, and one or more C=C double bonds are located on the chain more than 6 atoms but less than 17 atoms from the L1group;

[0121] d) no asymmetric carbon atoms are present in the compound in the moiety -C(A)(A')-CH2-L2-R2.

[0122] e)

[0123] In some preferred embodiments, two or more of the following apply (e.g., three or more):

[0124] a) Rl is a saccharide group or a derivative thereof, wherein Rl contains a saccharide group and the saccharide is selected from the group consisting of galactose, glucose, and mannose, and derivatives thereof;

[0125] b) the compound contains no glycosidic linkage;

[0126] c) two or more C=C double bonds are contained in the -C(A)(A')-CH2-L2-R2 moiety of the compound, and have one or more C=C double bonds located more than 8 atoms and less than 17 atoms up the chain from the L1 group;

[0127] d) no asymmetric carbon atoms are present in the compound in the moiety -C(A)(A')-CH2-L2-R2.

[0128] In some preferred embodiments, two or more of the following apply (e.g., three or more):

[0129] a) Rl is a saccharide group or a derivative thereof, wherein Rl contains a saccharide group and the saccharide is selected from the group consisting of galactose, glucose, and mannose, and derivatives thereof;

[0130] b) the compound contains no glycosidic linkage;

[0131] c) two or more C=C double bonds are contained in the -C(A)(A')-CH2-L2-R2 moiety of the compound, and have one or more C=C double bonds located more than 8 atoms and less than 17 atoms up the chain from the L1 group;

[0132] d) no asymmetric carbon atoms are present in the compound in the moiety -C(A)(A')-CH2-L2-R2.

[0133] In one embodiment, the compound of formula I can be a compound of formula la

[0134]

[0135] or a pharmaceutically acceptable salt thereof,

[0136] wherein:

[0137] Rl is selected from sugar groups or their derivatives, hydrogen, C1-C24 alkyl or C1-C24 derivatives of alkyl groups, C2-C24 alkenyl or C2-C24 derivatives of alkenyl groups, and C2-C24 alkynyl or C2-C24 derivatives of alkynyl groups.

[0138] L1 is a linking group;

[0139] L2 is a linking group;

[0140] R2 is selected from hydrogen, C1-C24 alkyl or C1-C24 derivatives of alkyl groups, C2-C24 alkenyl or C2-C24 derivatives of alkenyl groups, and C2-C24 alkynyl or C2-C24 derivatives of alkynyl groups.

[0141] L3 is a linking group; and

[0142] R3 is selected from hydrogen, C1-C24 alkyl or alkyl group C1-C24 derivatives, C2-C24 alkenyl or alkenyl group C2-C24 derivatives, and C2-C24 alkynyl or alkynyl group C2-C24 derivatives.

[0143] Furthermore, one or both of R2 and R3 are C10-C24 derivatives of alkyl or alkyl groups, C10-C24 derivatives of alkenyl or alkenyl groups, or C10-C24 derivatives of alkynyl or alkynyl groups.

[0144] In one embodiment, the compound of formula I may be a compound of formula Ia or a pharmaceutically acceptable salt thereof.

[0145]

[0146] in:

[0147] Rl is selected from sugar groups or their derivatives, hydrogen, C1-C24 alkyl groups or their derivatives, C2-C24 alkenyl groups or their derivatives, and C2-C24 alkynyl groups or their derivatives;

[0148] L1 is a linking group;

[0149] L2 is a linking group;

[0150] R2 is selected from hydrogen, C1-C24 alkyl or derivatives thereof, C2-C24 alkenyl or derivatives thereof, and C2-C24 alkynyl or derivatives thereof;

[0151] L3 is a linking group; and

[0152] R3is selected from the group consisting of hydrogen, a C1-C24alkyl group or derivatives thereof, a C2-C24alkenyl group or derivatives thereof, and a C2-C24alkynyl group or derivatives thereof;

[0153] and wherein one or both of R2and R3is a C10-C24alkyl, alkenyl, or alkynyl group or derivatives thereof.

[0154] In one embodiment, the compound of Formula la is not:

[0155]

[0156] In general, the above components regarding the preferred / optional embodiments of Formula I apply equally to Formula la, except where clearly inapplicable.

[0157] Preferably, in Formula la:

[0158] Rl is selected from the group consisting of a sugar group or derivatives thereof, a C1-C24alkyl group or derivatives thereof, a C2-C24alkenyl group or derivatives thereof, and a C2-C24alkynyl group or derivatives thereof;

[0159] L1is a linking group;

[0160] L2is a linking group;

[0161] R2is selected from the group consisting of hydrogen, a C1-C24alkyl group or derivatives thereof, a C2-C24alkenyl group or derivatives thereof, and a C2-C24alkynyl group or derivatives thereof;

[0162] L3is a linking group; and

[0163] R3is selected from the group consisting of hydrogen, a C1-C24alkyl group or derivatives thereof, a C2-C24alkenyl group or derivatives thereof, and a C2-C24alkynyl group or derivatives thereof;

[0164] and wherein one or both of R2and R3is a C10-C24alkyl, alkenyl, or alkynyl group or derivatives thereof.

[0165] More preferably, in Formula la:

[0166] Rl is a sugar group or derivatives thereof;

[0167] L1is a linking group;

[0168] L2is a linking group;

[0169] R2is selected from the group consisting of hydrogen, a C3-C24alkyl group or derivatives thereof, a C2-C24alkenyl group or derivatives thereof, and a C2-C24alkynyl group or derivatives thereof;

[0170] L3is a linking group; and

[0171] R3 is selected from hydrogen, C1-C24 alkyl or derivatives thereof, C2-C24 alkenyl or derivatives thereof, and C2-C24 alkynyl or derivatives thereof;

[0172] One or both of R2 and R3 are C10-C24 alkyl, alkenyl, or alkynyl groups or their derivatives.

[0173] More preferably, in formula Ia:

[0174] Rl is a sugar group or a derivative thereof;

[0175] L1 is a linking group;

[0176] L2 is a linking group;

[0177] R2 is a C10-C24 alkyl, alkenyl, or alkynyl group or a derivative thereof;

[0178] L3 is a linking group; and

[0179] R3 is a C10-C24 alkyl, alkenyl, or alkynyl group or a derivative thereof.

[0180] In Formula I and Formula Ia, the R1 group is selected from sugar groups or derivatives thereof, hydrogen, C1-C24 alkyl groups or derivatives thereof, C2-C24 alkenyl groups or derivatives thereof, and C2-C24 alkynyl groups or derivatives thereof. Preferably, the R1 group has at least 3 carbon atoms, or at least 4 carbon atoms, for example, 4-24 carbon atoms, 5-20 carbon atoms, or 6-18 carbon atoms. In a preferred embodiment, the R1 group has at least 6 carbon atoms, for example, 6-12 carbon atoms.

[0181] In one embodiment of Formula I and Formula Ia, the R1 group is selected from sugar groups or derivatives thereof, C10-C24 alkyl groups, alkenyl or alkynyl groups or derivatives thereof.

[0182] In Formulas I and Ia, in one embodiment, the R1 group is a sugar group or a derivative thereof. Those skilled in the art will understand that when the R1 group is a sugar group, it may include a sugar group or a derivative thereof. Such a group may be linked to the remainder of the molecule via a glycoside linker.

[0183] The sugar group can suitably be an α-glycoside or a β-glycoside. However, it is not necessary for the sugar group (or its derivative) to be linked to the rest of the molecule via a glycoside linker.

[0184] In one embodiment, the compound does not include a glycoside linker. This results in slower product degradation because it lacks anodic end positions that can be easily cleaved. Products that are more difficult to cleave will be more stable. Options for the linker L1 are shown below, and it can be seen that these include linker groups such as alkylene groups, and therefore they are non-glycoside groups.

[0185] The sugar group can be an L-stereoisomer or a D-stereoisomer.

[0186] In Formulas I and Ia, the sugar group R1 can be unprotected or protected; in other words, it can have all hydroxyl groups in free form, or some or all of the hydroxyl groups may have been converted to protected forms. Protecting groups for the hydroxyl groups of the sugar are well known in the art and include, but are not limited to, esters, ethers, and silyl ethers. For example, ether protecting groups can include methyl ethers, triphenylmethyl ethers, triphenylmethyl ethers, methoxymethyl ethers, benzyl ethers, p-methoxybenzyl ethers, and tetrahydropyranyl ethers. Silyyl ether protecting groups can include ethers based on: trimethylsilyl, triethylsilyl, tripropylsilyl, tert-butyldimethylsilyl, and tert-butyldiphenylsilyl. Esters protecting groups can include trifluoroacetate, acetate, trimethylacetate, and benzoyl ester.

[0187] It should be understood that in some derivatives of sugar groups, adjacent hydroxyl groups can be linked by ester bonds, such as ORG, where R is an alkylene group, for example, a C1-C6 alkylene group, such as methylene or isopropylene. In some embodiments, two pairs of adjacent hydroxyl groups are linked in this manner.

[0188] Therefore, one type of derivative of the sugar group covered by this invention is a derivative in which one or more (e.g., two or more) of the hydroxyl groups are in a protected form. It is possible that all hydroxyl groups are in a protected form. Where more than one hydroxyl group is protected, the protecting groups may be the same or may be different. It is possible that all axially oriented hydroxyl groups are protected and / or it is possible that all equatorially oriented hydroxyl groups are protected.

[0189] In one embodiment, the sugar group R1 has one or more hydroxyl groups protected by an acetyl ester protecting group and / or a benzyl ether protecting group.

[0190] In one embodiment, the sugar group R1 has a hydroxyl group that is protected by an acetyl ester protecting group, a benzyl ether protecting group, or a combination thereof.

[0191] In one embodiment, the sugar group R1 has a hydroxyl group protected by an acetyl ester protecting group.

[0192] Another class of glycosidic derivatives covered by this invention are those in which one or more (e.g., two or more) of the hydroxyl groups have been converted to amide or amino groups. It is possible that only one or two hydroxyl groups are converted to amide or amino groups. It is possible that all hydroxyl groups are converted to amide or amino groups. In the case of more than one hydroxyl group conversion, the amide or amino group each is converted to may be the same or may be different. Examples of amino and amide groups include, but are not limited to, -NH2-, -NHMe, -NMe2-, -N(COMe)H, -N(COEt)H, and -N(COMe)Me.

[0193] Generally, it is possible that the sugar group derivative is a derivative in which one or more (e.g., two or more) hydroxyl groups have been converted into nitrogen-containing functional groups, such as azides, amines, or amides. The advantage of this derivatization is that the compound can then be immobilized for protein pull-down experiments.

[0194] It is also possible that one or more (e.g., two or more) of the hydroxyl groups are converted into alkyl groups, such as C1-C6 alkyl groups, like methyl or ethyl groups.

[0195] For example, it is possible that the sugar comprises a sugar having six carbon atoms and a hydroxyl group at the C6 position that has been modified to remove the free -OH group, for example, because the hydroxyl group has been converted into an alkyl group or a nitrogen-containing organic functional group, such as an azide or an amine or amide group (e.g., a cyclic sugar); the group may, for example, have up to three carbon atoms, such as 0, 1 or 2 carbon atoms, and in one embodiment, the hydroxyl group at C6 has been converted into an azide or amine group.

[0196] In Formulas I and Ia, the sugar group of R1 can be a monosaccharide or a disaccharide. Optionally, it can be an oligosaccharide or a polysaccharide. In a preferred embodiment, R1 can suitably be a monosaccharide, but the invention is not limited to this.

[0197] The sugar group is preferably cyclic. However, it can optionally be linear. It can have any suitable number of atoms in its ring, such as 3, 4, 5, 6, or 7; preferably 4, 5, or 6. It can have any suitable number of carbons in the sugar group, such as 3, 4, 5, 6, or 7; preferably 4, 5, or 6. In a preferred embodiment, R1 is a hexose. In another embodiment, it is a pentose or heptose. In yet another embodiment, it is a tetose.

[0198] The sugar may be, for example, selected from allose, acetose, glucose, mannose, gulose, idose, galactose, and talose. However, the invention is not limited to these sugars (and their derivatives).

[0199] In one embodiment, the sugar is selected from galactose, glucose, and mannose, as well as their derivatives.

[0200] In formulas I and Ia, in some preferred embodiments R1 is a galactoside or glucosinolate, or a derivative thereof; in other words, the sugar group is galactose or glucose. However, it can be other glycosides, such as fructose or glucuronic acid, or derivatives thereof.

[0201] In some embodiments, a galactose group or a derivative thereof may be preferred. In other embodiments, a glucose group or a derivative thereof, or a mannose group or a derivative thereof, may be preferred, as the use of these groups is seen to improve activity. In one embodiment, the sugar comprises a glucose group or a derivative thereof.

[0202] The R1 group can be α-D-glucosidyl and / or β-D-glucosidyl. It can also be α-L-glucosidyl and / or β-L-glucosidyl. Preferably, the glucosidyl group is linked to the remainder of the molecule via an -OCH2- group. However, it is possible, for example, that the linking group is an -O(CH2)2- group, an -O(CH2)3- group, an -O(CHOH)- group, or an -O(CHNH2)- group; furthermore, alternating linking groups L1 can be used, as discussed further below.

[0203] The R1 group can be α-D-galactosidyl and / or β-D-galactosylgalactosidyl, and it can be α-L-galactosidyl and / or β-L-galactosidyl. Preferably, the galactosidyl group is linked to the rest of the molecule via an -OCH2- group. However, it is possible, for example, that the linking group can be an -O(CH2)2- group, an -O(CH2)3- group, an -O(CHOH)- group, or an -O(CHNH2)- group. Furthermore, alternating linking groups L1 can be used, as discussed further below.

[0204] The R1 group can be α-D-mannosyl and / or β-D-mannosyl. It can also be α-L-mannosyl and / or β-L-mannosyl. Preferably, the mannosyl group is linked to the rest of the molecule via an -OCH2- group. However, it is possible, for example, that the linking group can be an -O(CH2)2- group, an -O(CH2)3- group, an -O(CHOH)- group, or an -O(CHNH2)- group. Furthermore, alternating linking groups L1 can be used, as discussed further below.

[0205] Generally, in Formula I and Formula Ia, L1 can be any linking group, provided that such linking group is divalent. Preferably, the L1 linking group has 1 to 18 carbon atoms, especially 1 to 12 carbon atoms, such as 1 to 6 carbon atoms, for example, 1, 2, 3 or 4 carbon atoms.

[0206] Examples of divalent linking groups include alkylene groups, cycloalkylene groups, alkenyl groups, ether groups, imino groups, carbonyl groups (including ester, amide, and phosphate groups), (hetero)arylene groups, amino groups, thioether groups, and divalent residues containing any of these divalent groups linked in tandem. The linking group may optionally be substituted with one or more hydroxyl, amino, and / or carboxyl groups. The linking group may be a glycoside linking group.

[0207] In one embodiment, the compound does not include a glycoside linker. This may result in slower product degradation because it lacks anterior terminal sites that can be easily cleaved. Products that are more difficult to enzymatically hydrolyze will be more stable. For example, the linker may optionally be a C1-18 alkylene group substituted with one or more hydroxyl, amino, and / or carboxyl groups; particularly a C1-12 or C1-6 alkylene group, such as a C1, C2, C3, or C4 alkylene group.

[0208] In one embodiment of Formula I and Formula Ia, the linker group contains at least one heteroatom selected from O, P, N, and S, and in one such embodiment, at least one such heteroatom is located in the main chain of the linker group, rather than as a branch or substituent. For example, the linker group may be an ester, ether, thioether, amino, or phosphate-containing linker group.

[0209] Specific examples of linking groups containing one or more heteroatoms and wherein one or more of the heteroatoms are located in the main chain of the linking group include: -OCH2-, -O(CH2)2-, -O(CH2)3-, -O(CHOH), -O(CHOH)CH2, -O(CHNH2)-, -O(CHNH2)CH2-, -(CH2)COO(CH2)-, -S(CH2)-, -(CH2)S(CH2)-, -O(PO2)O(CH2)- and -O(PO2)O(CH2)2-.

[0210] In one embodiment, in formulas I and Ia, L1 is a linking group selected from the following groups:

[0211] (i) C1-C12 alkylene linkages, such as C1-C8 alkylene linkages, such as methylene, ethylene, propylene, butylene, or pentylene;

[0212] (ii) Ether linkage groups, such as -(CH2) p O(CH2) q - where p and q independently represent integers from 0 to 3, for example, 1 to 3;

[0213] (iii) C2-C6 alkenyl linkages, such as vinylidene;

[0214] (iv) Contains a carbonyl linking group, especially an ester linking group, such as -(CH2). p COO(CH2) q -, or -(CH2) P OC(=O)(CH2) q - where p and q independently represent integers from 0 to 3, for example, 1 to 3;

[0215] (v) (Miscellaneous) aryl linker, such as -(CH2) p (Ar)(CH2) q - where p and q independently represent integers from 0 to 3, for example, from 1 to 3, while Ar is a C6-C8 arylene substituent group, such as phenylene, or a 5 to 8-membered heteroarylene substituent group, such as furanyl, thiophene, or pyridinyl.

[0216] (vi) The amine linker of the formula -RxN(Rz)Ry-, for example, in which Rx and Ry are independently C1-C4 alkylene groups and Rz is H or C1-C4 alkyl, such as -CH2N(CH3)CH2-;

[0217] (vii) Thioether linkages, such as -(CH2) P S(CH2) q - where p and q independently represent integers from 0 to 3, for example, from 1 to 3;

[0218] (viii) Glycoside linker, such as an X-R4 group, where R4 is a C1-C12 alkyl, cycloalkyl, alkenyl, or alkynyl group and X is -O-, -PR a -、-NR a -、-S- or -CR a R b -, where R a and R b The group consisting of hydrogen and C1-C4 alkyl groups is selected independently.

[0219] In one embodiment, in formulas I and Ia, L1 is a linking group selected from the following groups:

[0220] (i) C1-C6 alkylene linkages, for example, C1-C5 alkylene linkages, such as methylene or ethylene;

[0221] (ii) Ether linkage groups, such as -(CH2) p O(CH2) q - where p and q independently represent integers from 1 to 3, and p+q equals 4 or less;

[0222] (iii) C2-C4 alkenyl linkages, such as vinylidene;

[0223] (iv) Ester linker -(CH2) p COO(CH2) q -or-(CH2) p OC(=O)(CH2) q - where p and q independently represent integers from 1 to 3, and p+q equals 4 or less;

[0224] (v) An amine linker of the formula -RxN(Rz)Ry-, for example, wherein Rx and Ry are C1-C4 alkylene, for example, C1 or C2 alkylene, and Rz is H or C1-C4 alkyl, for example, C1 or C2 alkyl;

[0225] (vi) Thioether linkages, such as -(CH2) p S(CH2) q - where p and q independently represent integers from 1 to 3, and p+q equals 4 or less;

[0226] (vii) Glycoside linker, such as the X-R4 group, where R4 is a C1-C12 alkyl, cycloalkyl, alkenyl, or alkynyl group and X is -O-, -PR a -、-NR a -、-S- or -CR a R b -, where R a and R b It is independently selected from the group consisting of hydrogen and C1-C4 alkyl groups.

[0227] In one embodiment, in formulas I and Ia, L1 is a linking group selected from the following groups:

[0228] (i) C1-C4 alkylene linkages, such as methylene or ethylene;

[0229] (ii) Ether linkage groups, such as -(CH2) p O(CH2) q - where p and q independently represent integers from 1 to 3, and p+q equals 4 or less;

[0230] (iii) C2-C4 alkenyl linkages, such as vinylidene;

[0231] (iv) Ester linker -(CH2)p COO(CH2) q -, or -(CH2) p OC(=O)(CH2) q - where p and q independently represent integers from 1 to 3, and p+q equals 4 or less;

[0232] (v) An amine linker of the formula -RxN(Rz)Ry-, for example, wherein Rx and Ry are C1-C4 alkylene, for example, C1 or C2 alkylene, and Rz is H or C1-C4 alkyl, for example, C1 or C2 alkyl;

[0233] (vi) Thioether linkages, such as -(CH2) p S(CH2) q - where p and q independently represent integers from 1 to 3, and p+q equals 4 or less;

[0234] (vii) Glycoside linker, such as the X-R4 group, where R4 is a C1-C12 alkyl, cycloalkyl, alkenyl, or alkynyl group and X is -O-, -PR a -、-NR a -、-S- or -CR a R b -, where R a and R b The group consisting of hydrogen and C1-C4 alkyl groups is selected independently.

[0235] In Formulas I and Ia, L1 is preferably a linking group that is a C1-C12 alkylene linking group or a glycoside linking group, or an ester linking group having 1 to 12 carbon atoms; more preferably, a C1-C8 alkylene linking group or a glycoside linking group having 1 to 8 carbon atoms or an ester linking group having 1 to 8 carbon atoms; most preferably, a C1-C6 alkylene linking group or a glycoside linking group having 1 to 6 carbon atoms or an ester linking group having 1 to 6 carbon atoms; such as a C1-C4 (e.g., C1 or C2) alkylene linking group or a glycoside linking group having 1 to 4 carbon atoms (e.g., C1 or C2) or an ester linking group having 1 to 4 carbon atoms (e.g., C2 or C3).

[0236] In some embodiments, L1 is preferably a C1-C12 alkylene linkage group or glycoside linkage group or ester linkage group, more preferably a C1-C8 alkylene linkage group or glycoside linkage group.

[0237] In one embodiment, in Formula I and Formula Ia, the alkylene linking group is straight-chain; in another embodiment, the linking group is a branched alkylene group. For example, L1 can represent a linking group that is a C1-C12 straight-chain alkylene linking group (such as a C1-C8 or C1-C6 straight-chain alkylene linking group) or a C2-C12 branched alkylene linking group (such as a C2-C8, C2-C6, or C3-C6 branched alkylene linking group).

[0238] Preferably, in Formulas I and Ia, L1 represents a C1-C6 alkylene linking group or a glycoside linking group, more preferably a C1-C5 alkylene linking group or a glycoside linking group. Therefore, it can be methylene, ethylene, propylene, butylene, or pentylene, or a glycoside linking group. In one embodiment, L1 represents a C1-C4 alkylene linking group, such as methylene, ethylene, or propylene, or a glycoside linking group.

[0239] In Formulas I and Ia, the L1 linker can be a glycoside linker, such as an X-R4 group, wherein R4 is a C1-C12 (e.g., C1-8, C1-6, or C1-4) alkyl, C4-C12 (e.g., C4-8, or C4-6) cycloalkyl, C2-C12 (e.g., C2-8, C2-6, or C2-4) alkenyl, or C2-C12 (e.g., C2-8, C2-6, or C2-4) alkynyl group, and X is -O-, -O(PO2)O-, or -NR. a -,-NR a C(=O)-,-PR a -, -S- or -CR a R b -, where R a and R b The group consisting of hydrogen and C1-C4 alkyl groups is selected independently.

[0240] Therefore, the R1 group can be linked to the rest of the molecule via a group X-R4, where X is based on an O, N, S, P, or C atom. Thus, O-glycosidic linkages, glycosylamine bonds, thioglycosidic linkages, P-glycosidic linkages, or C-glycosidic linkages can be present. When the group is -NR... a -or-PR a - At that time, R a Selected from the group consisting of hydrogen and C1-C4 alkyl groups; for example, it can be hydrogen or methyl. When the group is -CR a R b - At that time, R a and R b The group consisting of hydrogen and C1-C4 alkyl groups is selected independently; for example, each can be hydrogen or methyl.

[0241] It is possible that the glycoside linker is a linker of the formula -X-R4-, wherein R4 is a C1-C4 (e.g., C1, 2, or 3) alkyl, C4-C8 (e.g., C4, 5, or 6) cycloalkyl, or C2-C6 (e.g., C2, 3, or 4) alkenyl, and X is -O-, -O(PO2)O-, or -NR. a -、-S- or -CR a R b -, where R a and R b The group consisting of hydrogen and C1-C4 alkyl groups is selected independently.

[0242] In one embodiment, the glycoside linker is a linker of the formula -X-R4-, wherein R4 is a C1-C4 (e.g., C1, 2, or 3) alkyl or a C2-C6 (e.g., C2, 3, or 4) alkenyl, and X is -O-, -O(PO2)O-, or -NR. a - or -S-, where R a Choose from the group consisting of hydrogen and C1-C4 alkyl groups.

[0243] In one embodiment, the sugar group of R1 is linked to the remainder of the molecule via an O-glycoside linker. In such an embodiment, the sugar group of R1 is linked via an O-(CH2) linker. n The group is attached to the remainder of the molecule, where n is an integer from 1 to 6. n can be 1, 2, 3, 4, 5, or 6. Preferably, n is 1 to 4, for example, 1, 2, or 3. In one embodiment, n is 1 or 2; preferably, n is 1.

[0244] In Formula I, R2 is selected from hydrogen, C1-C24 alkyl or alkyl group C1-C24 derivatives, C2-C24 alkenyl or alkenyl group C2-C24 derivatives, and C2-C24 alkynyl or alkynyl group C2-C24 derivatives.

[0245] In formula Ia, R2 is selected from hydrogen, C1-C24 alkyl or derivatives thereof, C2-C24 alkenyl or derivatives thereof, and C2-C24 alkynyl or derivatives thereof.

[0246] Preferably, the R2 group contains one or more C=C double bonds; for example, it may contain two or more C=C double bonds or three or more C=C double bonds. In one embodiment, the R2 group has 1 to 8 C=C double bonds, such as 1 to 6 C=C double bonds.

[0247] R2 can be selected from hydrogen, C2-C24 alkyl or its derivatives, C2-C24 alkenyl or its derivatives and C2-C24 alkynyl or its derivatives, or it can be selected from hydrogen, C6-C24 alkyl or its derivatives, C6-C24 alkenyl or its derivatives and C6-C24 alkynyl or its derivatives.

[0248] R2 is preferably a C10-C24 alkyl, alkenyl, or alkynyl group, or a derivative thereof. More preferably, R2 is a C10-C20 alkyl, alkenyl, or alkynyl group, or a derivative thereof, such as a C10-C18 or C12-C18 alkyl, alkenyl, or alkynyl group, or a derivative thereof. It can be, for example, a C12-C24 group, a C12-C20 group, a C13-C20 group, or a C14-C20 group.

[0249] In one embodiment, R2 may be a C10-C24 derivative of an alkyl, alkenyl, or alkynyl group. Preferably, R2 is a C10-C20 derivative of an alkyl, alkenyl, or alkynyl group, such as a C10-C18 or C12-C18 derivative of an alkyl, alkenyl, or alkynyl group, which may, for example, be a C12-C24 group, a C12-C20 group, or a C13-C20 group. In such embodiments, the alkyl, alkenyl, or alkynyl group need not be the sole provider of the carbon atoms satisfying the scope; carbon atoms may also be formed by modification of these groups to form the derivative. In the embodiments to which this applies, the derivatives of alkyl, alkenyl, or alkynyl groups covered by the invention are those in which one or more (e.g., two or more) hydrogen atoms in the hydrocarbon chain are replaced by substituent groups and where such substituent groups comprise one or more carbon atoms.

[0250] In all embodiments contemplated for derivatives of alkyl, alkenyl, or alkynyl groups, the derivative of an alkyl, alkenyl, or alkynyl group covered by the present invention is a derivative in which one or more carbon atoms (e.g., two or more) in the hydrocarbon chain are replaced with heteroatoms. The heteroatoms may, for example, be selected from O, N, S, SO2, P, B, Si, and combinations thereof. For example, the heteroatoms may be selected from O, N, S, and combinations thereof. In one embodiment, one to five carbon atoms in the group are replaced with heteroatoms; for example, one, two, or three carbon atoms in the group may be replaced with heteroatoms. When more than one carbon atom in the group is replaced, the heteroatoms used may be the same or different.

[0251] Therefore, for example, the R2 group may include ether, amine, thioether, sulfone and / or sulfonamide groups in the chain.

[0252] Obviously, in the embodiments of the derivative in which one or more atoms in the hydrocarbon chain are replaced by heteroatoms, the number of carbon atoms in the alkyl, alkenyl, or ynyl group of R2 will be reduced. However, those skilled in the art will readily see how many carbon atoms would be in the hydrocarbon chain if one or more of these carbon atoms were not replaced by heteroatoms.

[0253] Furthermore, in all embodiments contemplated as derivatives of alkyl, alkenyl, or alkynyl groups, another derivative of the alkyl, alkenyl, or alkynyl group covered by the present invention is a derivative in which one or more (e.g., two or more) hydrogen atoms in the hydrocarbon group are substituted with a substituent. In one embodiment, 1 to 10 hydrogen atoms in the group, such as 1 to 6 in the hydrocarbon chain, for example, 1, 2, 3, or 4 hydrogen atoms, may be substituted with a substituent group. When more than one hydrogen atom in the group is substituted, the substituent groups used may be the same or different.

[0254] For example, the alkyl, alkenyl, or alkynyl group may optionally be replaced by one or more substituent groups independently selected from hydroxyl and amino and carboxyl groups, as well as aryl or heteroaryl groups (especially unsaturated ring and heterocyclic groups having 5 to 10 atoms (e.g., 6 to 10 atoms) in their rings), such as imidazolyl, thiazolyl, thiophene, phenyl, tolyl, xylyl, pyridyl, pyrimidinyl, pyrazinyl, indolyl, or naphthyl groups.

[0255] It is possible that the alkyl, alkenyl, or alkynyl group may be optionally substituted by one or more substituent groups selected from hydroxyl, amino, and carboxyl groups.

[0256] It is possible that the alkyl, alkenyl, or alkynyl groups may be optionally substituted with one or more independent unsaturated ring and heterocyclic groups selected from aryl or heteroaryl, particularly having 5 to 10 atoms (e.g., 6 to 10 atoms), such as imidazolyl, thiazolyl, thiophene, phenyl, tolyl, xylyl, pyridyl, pyrimidinyl, pyrazinyl, indolyl, or naphthyl substituents. The ring itself may, for example, be substituted with one or more C1-6 alkyl groups, such as one or two (or more) methyl or ethyl groups, as in the case of tolyl and xylyl. Preferably, the total number of carbon atoms in each of the substituent groups is 5 to 12.

[0257] In one embodiment, the R2 group is a substituted alkenyl group; for example, it can be (alkyl)-CHOH-(alkenyl), (alkyl)-CHNH2-(alkenyl), (alkenyl)-CHOH-(alkenyl) or (alkenyl)-CHNH2-(alkenyl).

[0258] It is possible that the total number of carbon atoms in the substituted alkenyl group is 10 to 24, such as 10 to 20, 10 to 18, or 12 to 18.

[0259] In one embodiment, the R2 group is a substituted alkyl group; for example, it can be substituted with one or more substituent groups independently selected from unsaturated cyclic and heterocyclic groups having 5 to 10 atoms (e.g., 6 to 10 atoms) in their ring. Preferably, it is an alkyl group substituted with two or more substituents independently selected from unsaturated cyclic and heterocyclic groups having 5 to 10 atoms (e.g., 6 to 10 atoms) in their ring. In one embodiment, the substituent group is an unsaturated cyclic group having 5 to 10 atoms (e.g., 6 to 10 atoms) in its ring and a total number of carbon atoms of 5 to 12, such as phenyl, naphthyl, tolyl, or xylylyl.

[0260] In one embodiment, R1 is two substituent groups on the same carbon atom in the alkyl group, and preferably these two substituent groups are the same.

[0261] In one embodiment, R2 is a C10-C24 derivative of an alkyl group, wherein the alkyl group is a C1-12 group and is substituted with one or more C5-12 substituent groups independently selected from aryl or heteroaryl groups, particularly unsaturated rings and heterocyclic groups having 5 to 10 atoms (e.g., 6 to 10 atoms) in their rings. Therefore, the total number of carbon atoms in the R2 group is C10-C24, and it consists of carbon atoms from the alkyl group and carbon atoms from the aryl or heteroaryl substituent groups.

[0262] In one embodiment, R2 is a C10-C20 derivative of an alkyl group, such as a C10-C18 or C12-C18 derivative of an alkyl group. It can be, for example, a C12-C24 group, a C12-C20 group, or a C13-C20 group.

[0263] It is possible that the alkyl group is a C1-8 group and this is replaced by one or more substituent groups independently selected from aryl or heteroaryl groups, particularly unsaturated rings and heterocyclic groups having 5 to 10 atoms (e.g., 6 to 10 atoms) in their rings. Preferably, the alkyl group is a C1-6 group (e.g., C1, C2, C3, or C4) and this is replaced by one or more substituent groups independently selected from aryl or heteroaryl groups, particularly unsaturated rings and heterocyclic groups having 5 to 10 atoms (e.g., 6 to 10 atoms) in their rings.

[0264] In one embodiment, the substituent group in the derivative of the alkyl group is selected from unsaturated cyclic groups having 5 to 10 atoms (e.g., 6 to 10 atoms) in their ring, such as phenyl, naphthyl, tolyl, or xylyl groups, particularly unsaturated cyclic groups having 6 atoms in their ring, such as phenyl, tolyl, or xylyl groups.

[0265] In Formula I and Formula Ia, the R2 group is unsubstituted in one embodiment.

[0266] In Formulas I and Ia, it is possible that one or more (e.g., two or more) carbon atoms in the hydrocarbon chain in R2 are replaced with heteroatoms, and one or more (e.g., two or more) hydrogen atoms in the hydrocarbon chain are replaced with substituent groups. Therefore, for example, the R2 group may include an amide or anhydride group in the chain.

[0267] The alkyl, alkenyl, or alkynyl groups can be straight-chain or branched; in one embodiment, the alkyl, alkenyl, or alkynyl groups are straight-chain.

[0268] In one embodiment of Formula I and Formula Ia, the R2 group is a C10-C24 alkenyl group or a C12-C24 alkenyl group, such as a C12-C20 alkenyl group or a C14-C20 alkenyl group.

[0269] In Formulas I and Ia, when the R2 group is an alkenyl group (or a derivative thereof), it is possible that the C=C double bond is Z-configured (cis) or E-configured (trans). In cases where there is more than one double bond, they can all be Z-configured, or they can all be E-configured, or they can be a combination of Z-configured and E-configured double bonds. In one embodiment, all the C=C double bonds are Z-configured.

[0270] Preferably, R2 is a C10-C24 alkenyl group, and may be, for example, a straight-chain alkenyl group having 10 to 20 carbon atoms. Preferably, R2 is a C12-C18 alkenyl group.

[0271] In Formula I and Formula Ia, the R2 alkenyl group preferably has 1 to 5 C=C double bonds, such as 1 to 4 C=C double bonds, for example 1 to 3 C=C double bonds, such as 2 or 3 C=C double bonds.

[0272] In Formula I and Formula Ia, the R2 group is preferably an alkenyl group and the double bond (or each one) is located at position 5 or higher on the carbon atom of the chain, such as position 6 or higher, or position 7 or higher, and preferably the C=C double bond (or each one) is located at position 8 or higher.

[0273] More preferably, R2 is a C14-C18 alkenyl (e.g., C16 or C17 alkenyl) having 1 to 3 C=C double bonds, such as 2 or 3 C=C double bonds. For example, R2 can be a C17 alkenyl having three C=C double bonds.

[0274] In embodiments of Formula I and Ia, the alkenyl group is 8,11,14-heptadectrienyl. In one embodiment, all double bonds are Z-configured.

[0275] In Formulas I and Ia, generally speaking, L2 can be any linking group, provided that the linking group is divalent. Preferably, the L2 linking group has 1 to 18 carbon atoms, particularly 1 to 12 carbon atoms, such as 1 to 6 carbon atoms, for example 1, 2, 3 or 4 carbon atoms.

[0276] Examples of divalent linking groups include alkylene groups, cycloalkylene groups, alkenyl groups, ether groups, imino groups, carbonyl groups (including ester, amide, and phosphate groups), (hetero)arylene groups, amino groups, thioether groups, and divalent residues containing any of these divalent groups linked in tandem. The linking group may optionally be substituted, for example, with one or more hydroxyl, amino, and / or carboxyl groups.

[0277] In Formulas I and Ia, in one embodiment, the linking group contains at least one heteroatom selected from O, P, N, and S. In one such embodiment, at least one such heteroatom is located in the main chain of the linking group, rather than as a branch or substituent group. For example, the linking group may be an ester, ether, thioether, amide, amino, or phosphate-containing linking group.

[0278] Specific examples of linking groups containing one or more heteroatoms and wherein the one or more heteroatoms are located in the main chain of the linking group include: -OC(=O)-, -OC(=O)CH2-, -NHC(=O)-, -NHC(=O)CH2-, -N(CH2)C(=O)-, -N(CH2)C(=O)CH2-, -OCH2-, -O(CH2)2-, -O(CH2)3-, -O(CHOH)-, -O(CHOH)CH2-, -O(CHNH2)-, -O(CHNH2)CH2-, -(CH2)COO(CH2)-, -S(CH2)-, -(CH2)S(CH2)-, -O(PO2)O(CH2)- and -O(PO2)O(CH2)2-.

[0279] In formulas I and Ia, in one embodiment, L2 is a linking group selected from the following groups:

[0280] (i) C1-C12 alkylene linkages, for example, C1-C8 alkylene linkages, such as methylene, ethylene, propylene, butylene, or pentylene;

[0281] (ii) Ether linkage groups, such as -(CH2) p O(CH2) q- where p and q independently represent integers from 0 to 3, for example, 1 to 3;

[0282] (iii) C2-C6 alkenyl linkages, such as vinylidene;

[0283] (iv) Contains a carbonyl linking group; especially an ester linking group, such as -(CH2). p C(=O)O(CH2) q -, or -(CH2) P OC(=O)(CH2) q -, where p and q independently represent integers from 0 to 3, for example, 1 to 3, or amide linkage groups, such as -(CH2). p NRzC(=O)(CH2) q -, or -(CH2) p C(=O)NRz(CH2) q - where p and q independently represent integers from 0 to 3, for example, 1 to 3, and Rz is H or C1-C4 alkyl;

[0284] (v) (Miscellaneous) aryl linker, such as -(CH2) p (Ar)(CH2) q - where p and q independently represent integers from 0 to 3, for example, from 1 to 3, while Ar is a C6-C8 arylene substituent group, such as phenylene, or a 5 to 8-membered heteroarylene substituent group, such as furanyl, thiophene, or pyridinyl.

[0285] (vi) An amine linker of the formula -RxN(Rz)Ry-, for example, wherein Rx and Ry are independently C1-C4 alkylene groups and Rz is H or C1-C4 alkyl, such as -CH2N(CH3)CH2-;

[0286] (vii) Thioether linkages, such as -(CH2) p S(CH2) q - where p and q independently represent integers from 0 to 3, for example, from 1 to 3;

[0287] (viii) Glycoside linker, such as an X-R4 group, where R4 is a C1-C12 alkyl, cycloalkyl, alkenyl, or alkynyl group and X is -O-, -PR a -、-NR a -、-S- or -CR a R b -, where R a and R b It is independently selected from the group consisting of hydrogen and C1-C4 alkyl groups.

[0288] In formulas I and Ia, in one embodiment, L2 is a linking group selected from the following groups:

[0289] (i) C1-C6 alkylene linkages, for example, C1-C5 alkylene linkages, such as methylene or ethylene;

[0290] (ii) Ether linkage groups, such as -(CH2) p O(CH2) q - where p and q independently represent integers from 1 to 3, and p+q equals 4 or less;

[0291] (iii) C2-C4 alkenyl linkages, such as vinylidene;

[0292] (iv) Ester linking groups such as -(CH2) p C(=O)O(CH2) q -, or -(CH2) p OC(=O)(CH2) q - where p and q each independently represent an integer from 0 to 3, and p+q equals 4 or less, or an amide linkage group, such as -(CH2). p NRzC(=O)(CH2) q -, or -(CH2) p C(=O)NRz(CH2) q - where p and q independently represent integers from 0 to 3, and p+q equals 4 or less, while Rz is H or C1-C4 alkyl;

[0293] (v) An amine linker of the formula -RxN(Rz)Ry-, for example, wherein Rx and Ry are C1-C4 alkylene, for example, C1 or C2 alkylene, and Rz is H or C1-C4 alkyl, for example, C1 or C2 alkyl;

[0294] (vi) Thioether linkers such as -(CH2) p S(CH2) q - where p and q independently represent integers from 1 to 3, and p+q equals 4 or less.

[0295] In formulas I and Ia, in one embodiment, L2 is a linking group selected from the following groups:

[0296] (i) C1-C4 alkylene linkages, such as methylene or ethylene;

[0297] (ii) Ether linkage groups, such as -(CH2) p O(CH2) q - where p and q independently represent integers from 1 to 3, and p+q equals 4 or less;

[0298] (iii) C2-C4 alkenyl linkages, such as vinylidene;

[0299] (iv) Ester linkage groups, such as -(CH2) p C(=O)O(CH2) q -, or -(CH2) p OC(=O)(CH2) q - where p and q each independently represent an integer from 0 to 3, and p+q equals 4 or less, or an amide linkage group, such as -(CH2). p NRzC(=O)(CH2) q -, or -(CH2) p C(=O)NRz(CH2) q - where p and q independently represent integers from 0 to 3, and p+q equals 4 or less, while Rz is H or a C1-C3 alkyl group;

[0300] (v) An amine linker of the formula -RxN(Rz)Ry-, for example, wherein Rx and Ry are C3-C4 alkylene, for example, C1 or C2 alkylene, and Rz is H or C1-C4 alkyl, for example, C1 or C2 alkyl;

[0301] (vi) Thioether linkers such as -(CH2) p S(CH2) q - where p and q independently represent integers from 1 to 3, and p+q equals 4 or less.

[0302] In Formulas I and Ia, L2 is preferably a linking group belonging to a C1-C12 alkylene linking group, a C1-C12 ester linking group, or a C1-C12 amide linking group, more preferably a C1-C8 alkylene linking group, a C1-C8 ester linking group, or a C1-C8 amide linking group. In one embodiment, the alkylene linking group is straight-chain. In another embodiment, the linking group is a branched alkylene group. For example, L2 may represent a linking group belonging to a C1-C12 straight-chain alkylene linking group (such as a C1-C8 or C1-C6 straight-chain alkylene linking group), a C2-C12 branched alkylene linking group (such as a C2-C8 or C2-C6, or a C3-C6 branched alkylene linking group), a C1-C12 (such as a C1-C8 or C1-C6) ester group, or a C1-C12 (such as a C1-C8 or C1-C6) amide group.

[0303] In Formulas I and Ia, L2 preferably represents a C1-C6 alkylene linking group, a C1-C6 ester group, or a C1-C6 amide group, more preferably a C1-C5 alkylene linking group, a C1-C5 ester group, or a C1-C5 amide group, such as a C1-C4 alkylene linking group, a C1-C4 ester group, or a C1-C4 amide group. Therefore, it could be methylene, ethylene, propylene, butylene, or pentylene, or an ester linking group -(CH2). p C(=O)O(CH2) q -or-(CH2) p OC(=O)(CH2) a - where p and q each independently represent an integer from 0 to 3, especially 0, 1, or 2, and p+q equals 4 or less, especially 3 or less, or an amide group -(CH2). p NRzC(=O)(CH2) q -, or -(CH2) p C(=O)NRz(CH2) q - where p and q independently represent integers from 0 to 3, especially 0, 1 or 2, and p+q equals 4 or less, especially 3 or less, and Rz is H or C1-C3 alkyl, especially H or C1 alkyl.

[0304] In one embodiment, in Formula I and Formula Ia, L2 represents a C1-C4 alkylene linking group, such as methylene, ethylene, or propylene, or an ester linking group -(CH2). p C(=O)O(CH2) q -or-(CH2) p OC(=O)(CH2) q - where p and q each independently represent an integer from 0 to 3, especially 0, 1, or 2, while p+q equals 3 or less, especially 2 or less, or an amide group -(CH2). p NRzC(=O)(CH2) q -, or -(CH2) p C(=O)NRz(CH2) q - where p and q independently represent integers from 0 to 3, especially 0, 1 or 2, and p+q equals 3 or less, especially 2 or less, and Rz is a linking group of H or C1-C3 alkyl, especially H.

[0305] It is possible that the L2 linking group is an O-ester linking group, a C-ester linking group, an ether linking group, a carbonyl linking group, an amine linking group, an N-amide linking group, a C-amide linking group, a thioether linking group, or an alkylene linking group.

[0306] In formulas I and Ia, in one embodiment, L2 is -CH2-, -CH2CH2-, -CH2CH2CH2-, -OC(=O)-, -NH-, -C(=O)-, -C(=O)-CH2-, -O-CH2-C(=O)-, -C(=O)-O-, -NHC(=O)-, -C(=O)NH-, -O-, -CH2-NH-, -CH2-NH-CH2-, -S-, -S-CH2-, -CH2-S-CH2-, or -CH2-O.

[0307] In formulas I and Ia, in one embodiment, L2 is -OC(=O)-, -NH-, -C(=O)-, -C(=O)-CH2-, -O-CH2-C(=O)-, -C(=O)-O-, -NHC(=O)-, -C(=O)NH-, -O-, -CH2-NH-, -CH2-NH-CH2-, -S-, -S-CH2-, -CH2-S-CH2-, or -CH2-O.

[0308] In Formula I, R3 is selected from hydrogen, C1-C24 alkyl or alkyl group C1-C24 derivatives, C2-C24 alkenyl or alkenyl group C2-C24 derivatives, and C2-C24 alkynyl or alkynyl group C2-C24 derivatives.

[0309] In formula Ia, R3 is selected from hydrogen, C1-C24 alkyl or derivatives thereof, C2-C24 alkenyl or derivatives thereof, and C2-C24 alkynyl or derivatives thereof.

[0310] Preferably, the R3 group comprises one or more C=C double bonds; for example, it may contain two or more C=C double bonds or three or more C=C double bonds. In one embodiment, the R3 group has 1 to 8 C=C double bonds, such as 1 to 6 C=C double bonds.

[0311] R3 can be selected from hydrogen, C2-C24 alkyl or its derivatives, C2-C24 alkenyl or its derivatives and C2-C24 alkynyl or its derivatives, or it can be selected from hydrogen, C6-C24 alkyl or its derivatives, C6-C24 alkenyl or its derivatives and C6-C24 alkynyl or its derivatives.

[0312] R3 is preferably a C10-C24 alkyl, alkenyl, or alkynyl group, or a derivative thereof. More preferably, R3 is a C10-C20 alkyl, alkenyl, or alkynyl group, or a derivative thereof, such as a C10-C18 or C12-C18 alkyl, alkenyl, or alkynyl group, or a derivative thereof. It can be, for example, a C12-C24 group, a C12-C20 group, a C13-C20 group, or a C14-C20 group.

[0313] In one embodiment, R3 may be a C10-C24 derivative of an alkyl, alkenyl, or alkynyl group. Preferably, R3 is a C10-C20 derivative of an alkyl, alkenyl, or alkynyl group, such as a C10-C18 or C12-C18 derivative of an alkyl, alkenyl, or alkynyl group. It may be, for example, a C12-C24 group, a C12-C20 group, or a C13-C20 group. In such embodiments, the alkyl, alkenyl, or alkynyl group need not be the sole provider of carbon atoms satisfying the range; carbon atoms may also be contributed by modifying these groups to form the derivative. This applies to embodiments described below, wherein the derivatives of alkyl, alkenyl, or alkynyl groups covered by the invention are derivatives in which one or more (e.g., two or more) hydrogen atoms in the hydrocarbon chain are substituted with substituent groups and these substituent groups comprise one or more carbon atoms.

[0314] In all embodiments contemplated involving derivatives of alkyl, alkenyl, or alkynyl groups, the derivatives of alkyl, alkenyl, or alkynyl groups covered by this invention are derivatives in which one or more (e.g., two or more) carbon atoms in the hydrocarbon chain are replaced with heteroatoms. The heteroatoms may, for example, be selected from O, N, S, SO2, P, B, Si, and combinations thereof. For example, the heteroatoms may be selected from O, N, S, and combinations thereof. In one embodiment, 1 to 5 carbon atoms in the group are replaced with heteroatoms; for example, 1, 2, or 3 carbon atoms in the group may be replaced with heteroatoms. When more than one carbon atom in the group is replaced, the heteroatoms used may be the same or may be different.

[0315] Therefore, for example, the R3 group may contain ether, amine, thioether, sulfone, and / or sulfonamide groups in the chain.

[0316] It is obvious that in the embodiments of the derivative in which one or more carbon atoms in the hydrocarbon chain are replaced by heteroatoms, the number of carbon atoms in the alkyl, alkenyl, or ynyl group of R3 will be reduced. However, those skilled in the art will readily see how many carbon atoms would be in the hydrocarbon chain if one or more of these carbon atoms were not replaced by heteroatoms.

[0317] Furthermore, in all embodiments in which derivatives of alkyl, alkenyl, or alkynyl groups are contemplated, another derivative of the alkyl, alkenyl, or alkynyl groups covered by the invention is a derivative in which one or more (e.g., two or more) hydrogen atoms in the hydrocarbon group are replaced by a substituent. In one embodiment, 1 to 10 hydrogen atoms in the group, such as 1 to 6 in the hydrocarbon chain, for example, 1, 2, 3, or 4 hydrogen atoms, may be replaced by a substituent group. When more than one hydrogen atom in the group is replaced, the substituent groups used may be the same or different.

[0318] For example, the alkyl, alkenyl, or alkynyl group may optionally be replaced by one or more substituents independently selected from hydroxyl and amino and carboxyl groups, as well as aryl or heteroaryl groups (especially unsaturated rings and heterocyclic groups having 5 to 10 atoms (e.g., 6 to 10 atoms) in their rings), such as imidazolyl, thiazolyl, thiophene, phenyl, tolyl, xylyl, pyridyl, pyrimidinyl, pyrazinyl, indolyl, or naphthyl groups.

[0319] It is possible that the alkyl, alkenyl, or alkynyl group may be optionally substituted by one or more substituent groups selected from hydroxyl, amino, and carboxyl groups.

[0320] It is possible that the alkyl, alkenyl, or alkynyl group may be optionally substituted by one or more substituent groups independently selected from: aryl or heteroaryl, particularly unsaturated cyclic and heterocyclic groups having 5 to 10 atoms (e.g., 6 to 10 atoms), such as imidazolyl, thiazolyl, thiophene, phenyl, tolyl, xylyl, pyridyl, pyrimidinyl, pyrazinyl, indolyl, or naphthyl. The ring itself may be substituted, for example, by one or more C1-6 alkyl groups, such as one or two (or more) methyl or ethyl groups, as in the case of tolyl and xylyl. Preferably, the total number of carbon atoms in each substituent group is 5 to 12.

[0321] In one embodiment, the R3 group is a substituted alkenyl group; for example, it can be (alkyl)-CHOH-(alkenyl), (alkyl)-CHNH2-(alkenyl), or (alkenyl)-CHNH2-(alkenyl).

[0322] It is possible that the total number of carbon atoms in the substituted alkenyl group is 10 to 24, such as 10 to 20, 10 to 18, or 12 to 18.

[0323] In one embodiment, the R3 group is a substituted alkyl group; for example, it can be substituted with one or more substituent groups independently selected from unsaturated cyclic and heterocyclic groups having 5 to 10 atoms (e.g., 6 to 10 atoms) in their ring. Preferably, it is an alkyl group substituted with two or more substituents independently selected from unsaturated cyclic and heterocyclic groups having 5 to 10 atoms (e.g., 6 to 10 atoms) in their ring. In one embodiment, the substituent group is an unsaturated cyclic group having 5 to 10 atoms (e.g., 6 to 10 atoms) in its ring and a total number of carbon atoms of 5 to 12, such as phenyl, naphthyl, tolyl, or xylylyl.

[0324] In one embodiment, two substituent groups are present on the same carbon atom of the alkyl group, and preferably these two substituent groups are identical.

[0325] In one embodiment, R3 is a C10-C24 derivative of an alkyl group, wherein the alkyl group is a C1-12 group and is substituted with one or more C5-12 substituent groups independently selected from aryl or heteroaryl groups, particularly unsaturated rings and heterocyclic groups having 5 to 10 atoms (e.g., 6 to 10 atoms) in their rings. Therefore, the total number of carbon atoms in the R3 group is C10-C24, and this is composed of carbon atoms from the alkyl group and carbon atoms from the aryl or heteroaryl substituent groups.

[0326] In one embodiment, R3 is a C10-C20 derivative of an alkyl group, such as a C10-C18 or C12-C18 derivative of an alkyl group. It can be, for example, a C12-C24 group, a C12-C20 group, or a C13-C20 group.

[0327] It is possible that the alkyl group is a C1-8 group and this is substituted with one or more substituent groups independently selected from aryl or heteroaryl groups, particularly unsaturated rings and heterocyclic groups having 5 to 10 atoms (e.g., 6 to 10 atoms) in their rings. Preferably, the alkyl group is a C1-6 group (e.g., C1, C2, C3, or C4) and this is substituted with one or more substituent groups independently selected from aryl or heteroaryl groups, particularly unsaturated rings and heterocyclic groups having 5 to 10 atoms (e.g., 6 to 10 atoms) in their rings.

[0328] In one embodiment, the substituent group in the derivative of the alkyl group is selected from unsaturated cyclic groups having 5 to 10 atoms (e.g., 6 to 10 atoms) in their ring, such as phenyl, naphthyl, tolyl, or xylyl, especially unsaturated cyclic groups having 6 atoms in their ring, such as phenyl, naphthyl, tolyl, or xylyl.

[0329] In Formula I and Formula Ia, the R3 group is unsubstituted in one embodiment.

[0330] In Formulas I and Ia, it is possible that in R3, one or more (e.g., two or more) carbon atoms in the hydrocarbon chain are replaced by heteroatoms, and one or more (e.g., two or more) hydrogen atoms in the hydrocarbon chain are replaced by substituent groups. Thus, for example, the R3 group may include amide or anhydride groups in the chain.

[0331] The alkyl, alkenyl, or alkynyl groups may be straight-chain or branched; in one embodiment, the alkyl, alkenyl, or alkynyl groups are straight-chain.

[0332] In Formula I and Formula Ia, in one embodiment, the R3 group is a C10-C24 alkenyl group or a C12-C24 alkenyl group, such as a C12-C20 alkenyl group or a C14-C20 alkenyl group.

[0333] In Formulas I and Ia, when the R3 group is an alkenyl group (or a derivative thereof), it is possible that the C=C double bond is Z-configured (cis) or E-configured (trans). When more than one double bond is present, these may all be Z-configured, or they may all be E-configured, or a combination of Z-configured and E-configured double bonds may exist. In one embodiment, all the C=C double bonds are Z-configured.

[0334] Preferably, R3 is a C10-C24 alkenyl group and may be, for example, a straight-chain alkenyl group having 10 to 20 carbon atoms. More preferably, R3 is a C12-C18 alkenyl group.

[0335] In Formula I and Formula Ia, the R3 alkenyl group preferably has 1 to 5 C=C double bonds, such as 1 to 4 C=C double bonds, for example 1 to 3 C=C double bonds, such as 2 or 3 C=C double bonds.

[0336] In Formula I and Formula Ia, the R3 group is preferably an alkenyl group and the double bond (or each one) is located at carbon position 5 or higher in the chain, such as position 6 or higher, or position 7 or higher, and preferably the C=C double bond (or each one) is located at position 8 or higher.

[0337] More preferably, R3 is a C14-C18 alkenyl (e.g., C16 or C17 alkenyl) having 1 to 3 C=C double bonds, such as 2 or 3 C=C double bonds. For example, R3 can be a C17 alkenyl having three C=C double bonds.

[0338] In one embodiment of Formula I and Formula Ia, the alkenyl R3 is 8,11,14-heptadecyltrienyl. In one embodiment, all the double bonds are Z-configured.

[0339] In Formulas I and Ia, generally speaking, L3 can be any linking group, provided that the linking group is divalent. Preferably, the L3 linking group has 1 to 18 carbon atoms, especially 1 to 12 carbon atoms, such as 1 to 6 carbon atoms, for example, 1, 2, 3 or 4 carbon atoms.

[0340] Examples of divalent linking groups include alkylene groups, cycloalkylene groups, alkenyl groups, ether groups, imino groups, carbonyl groups (including ester, amide, and phosphate groups), (hetero)arylene groups, amino groups, thioether groups, and divalent residues containing any of these divalent groups linked in tandem. The linking group may optionally be substituted with, for example, one or more hydroxyl, amino, and / or carboxyl groups.

[0341] In Formulas I and Ia, in one embodiment, the linking group contains at least one heteroatom selected from O, P, N, and S. In one such embodiment, at least one such heteroatom is located in the main chain of the linking group, rather than as a branch or substituent group. For example, the linking group may be an ester, ether, thioether, amide, amino, or phosphate-containing linking group.

[0342] Specific examples of linking groups containing one or more heteroatoms (wherein one or more of the heteroatoms are located in the main chain of the linking group) include: -OC(=O)-, -OC(=O)CH2-, -NHC(=O)-, -NHC(=O)CH2-, -N(CH2)C(=O)-, -N(CH2)C(=O)CH2-, -OCH2-, -O(CH2)2-, -O(CH2)3-, -O(CHOH)-, -O(CHOH)CH2-, -O(CHNH2)-, -O(CHNH2)CH2-, -(CH2)COO(CH2)-, -S(CH2)-, -(CH2)S(CH2)-, -O(PO2)O(CH2)- and -O(PO2)O(CH2)2-.

[0343] In formulas I and Ia, in one embodiment, L3 is a linking group selected from the following groups:

[0344] (i) C1-C12 alkylene linkages, for example, C1-C8 alkylene linkages, such as methylene, ethylene, propylene, butylene, or pentylene;

[0345] (ii) Ether linkage groups, such as -(CH2) p O(CH2) q - where p and q independently represent integers from 0 to 3, for example, 1 to 3;

[0346] (iii) C2-C6 alkenyl linkages, such as vinylidene;

[0347] (iv) Containing a carbonyl linker group; especially an ester linker group, such as -(CH2). p C(=O)O(CH2) q -, or -(CH2) POC(=O)(CH2) q -, where p and q independently represent integers from 0 to 3, for example, 1 to 3, or amide linkage groups, such as -(CH2). p NRzC(=O)(CH2) q -, or -(CH2) p C(=O)NRz(CH2) q - where p and q independently represent integers from 0 to 3, for example, 1 to 3, and Rz is H or C1-C4 alkyl;

[0348] (v) (Miscellaneous) aryl linker, such as -(CH2) p (Ar)(CH2) q - where p and q independently represent integers from 0 to 3, for example, from 1 to 3, and Ar is a C6-C8 arylene substituent group, such as phenylene, or a 5 to 8-membered heteroarylene substituent group, such as furanyl, thiophene, or pyridinyl.

[0349] (vi) An amine linker of the formula -RxN(Rz)Ry-, for example, wherein Rx and Ry are independently C1-C4 alkylene groups and Rz is H or C1-C4 alkyl, such as -CH2N(CH3)CH2-;

[0350] (vii) Thioether linkages, such as -(CH2) p S(CH2) q - where p and q independently represent integers from 0 to 3, for example, from 1 to 3;

[0351] (viii) Glycoside linker, such as an X-R4 group, where R4 is a C1-C12 alkyl, cycloalkyl, alkenyl, or alkynyl group and X is -O-, -PR a -、-NR a -、-S- or -CR a R b -, where R a and R b The group consisting of hydrogen and C1-C4 alkyl groups is selected independently.

[0352] In formulas I and Ia, in one embodiment, L3 is a linking group selected from the following groups:

[0353] (i) C1-C6 alkylene linkages, for example, C1-C5 alkylene linkages, such as methylene or ethylene;

[0354] (ii) Ether linkage groups, such as -(CH2) p O(CH2) q - where p and q independently represent integers from 1 to 3, and p+q equals 4 or less;

[0355] (iii) C2-C4 alkenyl linkages, such as vinylidene;

[0356] (iv) Ester linking groups such as -(CH2) p C(=O)O(CH2) q -, or -(CH2) p OC(=O)(CH2) q - where p and q each independently represent an integer from 0 to 3, and p+q equals 4 or less, or an amide linkage group, such as -(CH2). p NRzC(=O)(CH2) q -, or -(CH2) p C(=O)NRz(CH2) q - where p and q independently represent integers from 0 to 3, and p+q equals 4 or less, while Rz is H or C1-C4 alkyl;

[0357] (v) An amine linker of the formula -RxN(Rz)Ry-, for example, wherein Rx and Ry are C1-C4 alkylene, for example, C1 or C2 alkylene, and Rz is H or C1-C4 alkyl, for example, C1 or C2 alkyl;

[0358] (vi) Thioether linkages, such as -(CH2) p S(CH2) q - where p and q independently represent integers from 1 to 3, and p+q equals 4 or less.

[0359] In formulas I and Ia, in one embodiment, L3 is a linking group selected from the following groups:

[0360] (i) C1-C4 alkylene linkages, such as methylene or ethylene;

[0361] (ii) Ether linkage groups, such as -(CH2) p O(CH2) q - where p and q independently represent integers from 1 to 3, and p+q equals 4 or less;

[0362] (iii) C2-C4 alkenyl linkages, such as vinylidene;

[0363] (iv) Ester linking groups such as -(CH2) p C(=O)O(CH2) q -, or -(CH2) p OC(=O)(CH2) q - where p and q each independently represent an integer from 0 to 3, and p+q equals 4 or less, or an amide linkage group, such as -(CH2). pNRzC(=O)(CH2) q -, or -(CH2) p C(=O)NRz(CH2) q - where p and q independently represent integers from 0 to 3, and p+q equals 4 or less, while Rz is H or C1-C4 alkyl;

[0364] (v) An amine linker of the formula -RxN(Rz)Ry-, for example, wherein Rx and Ry are C1-C4 alkylene, for example, C1 or C2 alkylene, and Rz is H or C1-C4 alkyl, for example, C1 or C2 alkyl;

[0365] (vi) Thioether linkages, such as -(CH2) p S(CH2) q - where p and q independently represent integers from 1 to 3, and p+q equals 4 or less.

[0366] In Formulas I and Ia, L3 is preferably a linking group belonging to a C1-C12 alkylene linking group, a C1-C12 ester linking group, or a C1-C12 amide linking group, more preferably a C1-C8 alkylene linking group, a C1-C8 ester linking group, or a C1-C8 amide linking group. In one embodiment, the alkylene linking group is straight-chain. In another embodiment, the linking group is a branched alkylene group. For example, L3 may represent a linking group belonging to a C1-C12 straight-chain alkylene linking group (such as a C1-C8 or C1-C6 straight-chain alkylene linking group), a C2-C12 branched alkylene linking group (such as a C2-C8, C2-C6, or C3-C6 branched alkylene linking group), a C1-C12 (such as a C1-C8 or C1-C6) ester group, or a C1-C12 (such as a C1-C8 or C1-C6) amide group.

[0367] In formulas I and Ia, L3 may represent a C1-C6 alkylene linkage, a C1-C6 ester linkage, or a C1-C6 amide linkage, more preferably a C1-C5 alkylene linkage, a C1-C5 ester linkage, or a C1-C5 amide linkage, such as a C1-C4 alkylene linkage, a C1-C4 ester linkage, or a C1-C4 amide linkage. Therefore, it could be methylene, ethylene, propylene, butylene, or pentylene, or an ester linkage -(CH2). p C(=O)O(CH2) q -or-(CH2) p OC(=O)(CH2) a -, where p and q each independently represent an integer from 0 to 3, especially 0, 1, or 2, while p+q equals 4 or less, especially 3 or less, or an amide group -(CH2). pNRzC(=O)(CH2) q -, or -(CH2) p C(=O)NRz(CH2) q - where p and q independently represent integers from 0 to 3, especially 0, 1 or 2, and p+q equals 4 or less, especially 3 or less, and Rz is H or C1-C3 alkyl, especially H or C1 alkyl.

[0368] In one embodiment of Formula I and Formula Ia, L3 represents a C1-C4 alkylene linking group, such as methylene, ethylene, or propylene, or an ester linking group -(CH2). p C(=O)O(CH2) q -or-(CH2) p OC(=O)(CH2) q - where p and q each independently represent an integer from 0 to 3, especially 0, 1, or 2, while p+q equals 3 or less, especially 2 or less, or an amide group -(CH2). p NRzC(=O)(CH2) q -, or -(CH2) p C(=O)NRz(CH2) q - where p and q independently represent integers from 0 to 3, especially 0, 1 or 2, and p+q equals 3 or less, especially 2 or less, and Rz is a linking group of H or C1-C3 alkyl, especially H.

[0369] In one implementation, in formulas I and Ia, L3 is equivalent to CH2-L2.

[0370] It is possible that the L3 linking group is an O-ester linking group, a C-ester linking group, an ether linking group, a carbonyl linking group, an amine linking group, an N-amide linking group, a C-amide linking group, a thioether linking group, or an alkyl linking group.

[0371] In formulas I and Ia, in one embodiment, L3 is -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2O-C(=O)-, -OC(=O)-, -NH-, -C(=O)-, -C(=O)-CH2-, -O-CH2-C(=O)-, -C(=O)-O-, -NHC(=O)-, -C(=O)NH-, -O-, -CH2-NH-, -CH2-NH-CH2-, -S-, -S-CH2-, -CH2-S-CH2- or -CH2-O.

[0372] In formulas I and Ia, in one embodiment, L3 is -CH2CH2-, -CH2CH2CH2-, -CH2O-C(=O)-, -CH2-NH-, -CH2-NH-CH2-, -CH2-S-CH2-; or -CH2-O.

[0373] In one embodiment, L3 is -OC(=O)-, -NH-, -C(=O)-, -C(=O)-CH2-, -O-CH2-C(=O)-, -C(=O)-O-, -NHC(=O)-, -C(=O)NH-, -O-, -CH2-NH-, -CH2-NH-CH2-, -S-, -S-CH2-, -CH2-S-CH2- or -CH2-O.

[0374] In Formulas I and Ia, in one embodiment, R2 and R3 may be the same or different, each being a C10-C24 alkyl, alkenyl, or alkynyl group, or a derivative thereof. Preferably, R2 and R3 may be the same or different, each being a C10-C20 alkyl, alkenyl, or alkynyl group, or a derivative thereof, such as a C10-C18 or C12-C18 alkyl, alkenyl, or alkynyl group, or a derivative thereof. It is possible, for example, that R2 and R3 may be the same or different, each being a C12-C24 group, a C12-C20 group, or a C14-C20 group.

[0375] In Formulas I and Ia, in one embodiment, R2 and R3 may be the same or different, each being a C10-C24 alkenyl (or a derivative thereof). For example, both R2 and R3 can preferably be straight-chain alkenyl groups having 10 to 20 carbon atoms, such as C12-C18 or C14-C18 straight-chain alkenyl groups. In one embodiment, all said double bonds are Z-configured. In one embodiment, R2 and R3 are both C10-C24 alkenyl groups having 1 to 5 C=C double bonds, for example, each of them independently is a C12-C18 straight-chain alkenyl group having 1 to 4 C=C double bonds, such as a C16, C17, or C18 straight-chain alkenyl group having 1 to 3 C=C double bonds, for example, 2 or 3 C=C double bonds.

[0376] In Formula I and Formula Ia, it is preferred that R2 and R3 are both C17 alkenyl groups having three C=C double bonds. More preferably, R2 and R3 are both 8,11,14-heptadecenetrienyl groups.

[0377] In formulas I and Ia, in one embodiment, L2 and L3 may be the same or different, each being an O-ester linking group. For example, L2 and L3 may preferably both be -OC (=O)- linking groups.

[0378] In a preferred embodiment, in Formula I and Formula Ia, L2 is an O-ester linking group and L3 is CH2-L2. For example, L2 may preferably be an -OC (=O)- linking group and L3 may be CH2-L2.

[0379] As used herein, the term "sugar" refers to a compound containing carbon, hydrogen, and oxygen atoms. A sugar group may contain atoms other than carbon, hydrogen, and oxygen, but must contain at least these types of atoms. The term "sugar" encompasses compounds in both cyclic and open-chain forms containing carbon, hydrogen, and oxygen. Therefore, compounds containing open chains, such as sorbitol and mannitol, are also covered by the term "sugar." However, cyclic sugars are preferred. The term "sugar" is intended to be used in its broadest sense to encompass sugars and sugars, such as, but not limited to, monosaccharides, disaccharides, oligosaccharides, and polysaccharides. Examples of sugar groups include, but are not limited to, D-arabinose, L-arabinose, D-ribose, L-ribose, D-xylose, L-xylose, D-glucose, L-glucose, D-fructose, L-fructose, D-galactose, L-galactose, D-mannose, L-mannose, D-atrosose, L-atrosose, D-aloose, L-aloose, D-gulose, L-gulose, D-iduroose, L-iduroose, D-taloose, L-taloose, D-sucrose, L-sucrose, and D-lactose.

[0380] As used herein, the term "alkyl" refers to a saturated straight-chain or branched alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, isopentyl, hexyl, heptyl, octyl, or nonyl.

[0381] As used herein, the term "alkenyl" refers to an unsaturated straight-chain or branched hydrocarbon group having one or more carbon-carbon double bonds. Examples of alkenyl groups include, but are not limited to, decenyl, dodecenyl, undecenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, and nonadecenyl.

[0382] As used herein, the term "alkynyl" refers to an unsaturated straight-chain or branched hydrocarbon group having one or more carbon-carbon triple bonds.

[0383] As used in this article, the term "hydroxyl" refers to -OH.

[0384] As used herein, the term "amino" refers to -NRR', where R and R' are independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, aryl, carbocyclic, and heterocyclic groups, or where R and R' can combine to form a heterocyclic group. Preferably, R and R' have 0 to 6 carbon atoms, such as 0 to 4 carbon atoms, for example 0, 1, or 2 carbon atoms.

[0385] As used herein, the term "amide group" refers to -N(COR)R', wherein R and R' are independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, aryl, carbocyclic, and heterocyclic groups. Preferably, R and R' have 0 to 6 carbon atoms, such as 0 to 4 carbon atoms, for example, 0, 1, or 2 carbon atoms.

[0386] As used herein, the term "carbonyl linking group" refers to a C(=O)- or -C(=O)-R" group, wherein R" is selected from the group consisting of alkyl, heteroalkyl, aryl, carbocyclic, and heterocyclic groups. Preferably, R" has 1 to 6 carbon atoms, such as from 1 to 4 carbon atoms, for example, 1 or 2 carbon atoms.

[0387] As used herein, the term "C-ester linker" refers to a C(=O)O- or -C(=O)OR"- group, wherein R" is selected from the group consisting of alkyl, alkenyl, heteroalkyl, aryl, carbocyclic, and heterocyclic groups. Preferably, R" has 1 to 6 carbon atoms, such as 1 to 4 carbon atoms, for example, 1 or 2 carbon atoms.

[0388] As used herein, the term "O-ester linker" refers to the -OC(=O)- or -OC(=O)R"- group, wherein R" is selected from the group consisting of alkyl, alkenyl, heteroalkyl, aryl, carbocyclic, and heterocyclic groups. Preferably, R" has 1 to 6 carbon atoms, such as 1 to 4 carbon atoms, for example, 1 or 2 carbon atoms.

[0389] As used herein, the term "C-amide linker" refers to a C(=O)NH- or -C(=O)NR"- group, wherein R" is selected from the group consisting of alkyl, alkenyl, heteroalkyl, aryl, carbocyclic, and heterocyclic groups. Preferably, R" has 1 to 6 carbon atoms, such as 1 to 4 carbon atoms, for example, 1 or 2 carbon atoms.

[0390] As used herein, the term "N-amide linker" refers to a -NHC(=O)- or -NR”C(=O)- group, wherein R” is selected from the group consisting of alkyl, alkenyl, heteroalkyl, aryl, carbocyclic, and heterocyclic groups. Preferably, R” has 1 to 6 carbon atoms, such as 1 to 4 carbon atoms, for example, 1 or 2 carbon atoms.

[0391] As used herein, the term "ether linking group" refers to -O-, -OR"-, R"-O-, or -R"-OR"- groups, wherein R" is selected from the group consisting of alkyl, alkenyl, heteroalkyl, aryl, carbocyclic, and heterocyclic groups. Preferably, R" has 1 to 6 carbon atoms, such as 1 to 4 carbon atoms, for example, 1 or 2 carbon atoms.

[0392] As used herein, the term "thioether linking group" refers to a -S-, -SR"-, R"-S-, or -R"-SR"- group, wherein R" is selected from the group consisting of alkyl, alkenyl, heteroalkyl, aryl, carbocyclic, and heterocyclic groups. Preferably, R" has 1 to 6 carbon atoms, such as 1 to 4 carbon atoms, for example, 1 or 2 carbon atoms.

[0393] Pharmaceutically acceptable salts may, for example, be one of those listed below: Handbook of Pharmaceutical Salts: Properties, Selection and Use, edited by PHStahl and CGWerrauth, Weinhems / Zürich: Wiley-VCH / VHCA, 2002.

[0394] The compounds of Formula I and Ia may contain one or more asymmetric carbon atoms (chiral centers) and are therefore capable of existing in racemic and optically active forms. This invention covers all stereoisomers of all compounds of Formula I. Therefore, optical isomers or enantiomers, racemates, diastereomers, and mixtures of diastereomers are also covered in the compounds of Formula I and Ia.

[0395] The present invention therefore relates to compounds of formula I or Ia, which may be in the form of enantiomers, diastereomers, racemates or mixtures of diastereomers, and may be provided in the form of pharmaceutically acceptable salts or solvates of the formula.

[0396] In one embodiment, the product is provided in the form of a diastereomer; such a mixture may have improved solubility properties, which in turn makes the compound easier to handle and easier to formulate into pharmaceutical compositions.

[0397] In one embodiment, the compound of formula I or Ia is a compound of the following formula:

[0398]

[0399] The groups R1, R2, R3, L1, L2 and L3 can take any of the above definitions.

[0400] In a preferred embodiment, the compound of formula I or Ia is a compound of the following formula:

[0401]

[0402] The groups R1, R2, R3||, L1, L2, and L3 can take any of the above definitions.

[0403] In one embodiment, the compound of formula I or Ia is a compound of the following formula:

[0404]

[0405] The groups R1, R2, and R3 can take any of the above definitions, while X is absent or -O-, -NR. a -、-S- or -CR a R b -, where R a and R b The group consisting of hydrogen and C1-C4 alkyl groups is chosen independently, and n is an integer from 1 to 6, for example, 1, 2 or 3.

[0406] In one implementation:

[0407] R1 is a sugar group or a derivative thereof;

[0408] X does not exist or is -O- or -NR a -、-S- or -CR a R b -, where R a and R b Independently selected from the group consisting of hydrogen and C1-C4 alkyl groups;

[0409] n is an integer from 1 to 6, for example, 1, 2 or 3;

[0410] R2 is a C10-C24 alkyl, alkenyl, or ynyl group or a derivative thereof; and

[0411] R3 is a C10-C24 alkyl, alkenyl, or alkynyl group or a derivative thereof;

[0412] In one embodiment, the compound of formula I or Ia is a compound of the following formula;

[0413]

[0414] The groups R1, R2, and R3 can be defined in any of the above ways, while X is absent or is -O-, -NRa-, -S-, or -CR. a R b -, where R a and R b The group consisting of hydrogen and C1-C4 alkyl groups is chosen independently, and n is an integer from 1 to 6, for example, 1, 2 or 3.

[0415] In one implementation:

[0416] R1 is a sugar group or a derivative thereof;

[0417] X does not exist or is -O-, -NRa-, -S-, or -CR. a R b -, where R a and R b Independently selected from the group consisting of hydrogen and C1-C4 alkyl groups;

[0418] n is an integer from 1 to 6, for example, 1, 2 or 3;

[0419] R2 is a C10-C24 alkyl, alkenyl, or ynyl group or a derivative thereof; and

[0420] R3 is a C10-C24 alkyl, alkenyl, or alkynyl group or a derivative thereof;

[0421] In one embodiment, the compound of formula I or Ia is a compound of the following formula:

[0422]

[0423] In one embodiment, the compound of formula I or Ia is 1,2-bis(octadecanotri-3-O-β-D-galactosidyl-sn-glycerol).

[0424] In one embodiment, the compound of formula I or Ia is C 45 H 74 O 10 .

[0425] In one embodiment, the compound of formula I or Ia is a compound of the following formula:

[0426] In one embodiment, the compound of formula I or Ia is C 53 H 82 O 14 .

[0427] In one embodiment, the compound of formula I or Ia is a compound of the following formula:

[0428]

[0429] In one embodiment, the compound of formula I or Ia is C 45 H 75 O 13 P.

[0430] In one embodiment, the compound of formula I or Ia is a compound of the following formula:

[0431]

[0432] In one embodiment, the compound of formula I or Ia is C45 H 73 O 10 N.

[0433] In one embodiment, the compound of formula I or Ia is a compound of the following formula:

[0434]

[0435] In one embodiment, the compound of formula I or Ia is C 45 H 75 O9N.

[0436] In one embodiment, the compound of formula I or Ia is a galactolipid, preferably a glycerolipid.

[0437] In one embodiment, the compound of formula I or Ia is 1,2-bis(octadecathitrenic)-O-β-D-galactosidyl-sn-glycerol.

[0438] In one embodiment, the compound of formula I or Ia is C 45 H 74 O 10 In another embodiment, the compound of formula I or Ia is C 53 H 82 O 14 .

[0439] In one embodiment, the compound of formula I or Ia is a compound of the following formula:

[0440]

[0441] In one embodiment, the compound of formula I or Ia is a compound of the following formula:

[0442]

[0443] In one embodiment, the compound of formula I or Ia is a compound of the following formula:

[0444]

[0445] In one embodiment, the compound of formula I or Ia is a compound of the following formula:

[0446]

[0447] In one embodiment, the compound of formula I or Ia is a compound of the following formula:

[0448]

[0449] In one embodiment, the compound of formula I or Ia is a compound of the following formula:

[0450] In one embodiment, the compound of formula I or Ia is a compound of the following formula:

[0451]

[0452] In one embodiment, the compound of formula I or Ia is a compound of the following formula:

[0453]

[0454] In one embodiment, the compound of formula I or Ia is a compound of the following formula:

[0455]

[0456] In one embodiment, the compound of formula I or Ia is a compound of the following formula:

[0457]

[0458] In one embodiment, the compound of formula I or Ia is a compound of the following formula:

[0459]

[0460] In one embodiment, the compound of formula I or Ia is a compound of the following formula:

[0461]

[0462] In one embodiment, the compound of formula I or Ia is a compound of the following formula:

[0463]

[0464] In one embodiment, the compound of formula I or Ia is a compound of the following formula:

[0465]

[0466] In one embodiment, the compound of formula I or Ia is a compound of the following formula:

[0467] In one embodiment, the compound of formula I or Ia is a compound of the following formula:

[0468]

[0469] In one embodiment, the compound of formula I or Ia is a compound of the following formula:

[0470]

[0471] In one embodiment, the compound of formula I or Ia is a compound of the following formula:

[0472]

[0473] In one embodiment, the compound of formula I or Ia is a compound of the following formula:

[0474]

[0475] In one embodiment, the compound of formula I or Ia is a compound of the following formula:

[0476]

[0477] In one embodiment, the compound of formula I or Ia is a compound of the following formula:

[0478] In one embodiment, the compound of formula I or Ia is a compound of the following formula:

[0479]

[0480] The compounds of the present invention may be composed of compounds selected from compounds 99, 218, 139, 184, 123, 180, 124, 159, 38, 215, 146, 122, 119, 62, 120, 46, 61, 57, 60, 56, 154, and 58 (e.g., ...). Figure 16 It consists of any compound in the group shown in 17.

[0481] The compounds of the present invention may be selected from compounds 99, 218, 139, 184, 123, 180, 124, 159, 215, 146, 122, 119, 62, 120, 46, 61, 57, 60, 56, 154 and 58 (e.g.) Figure 16 It consists of any compound in the group shown in 17.

[0482] The compounds of the present invention may be selected from compounds 99, 218, 139, 184, 123, 180, 124, 159, 215, 146, 122, 119, 62, 120 and 46 (e.g.) Figure 16 It consists of any one of the compounds in the group shown.

[0483] The compounds of the present invention may be selected from compounds 99, 218, 139, 184, 123, 180, 124, 122, 119, 62, 120 and 46 (e.g.) Figure 16 It consists of any one of the compounds in the group shown.

[0484] The compounds of the present invention may be selected from compounds 99, 218, 139, 184, 123, 180 and 124 (e.g. Figure 16 It consists of any one of the compounds in the group shown.

[0485] Compounds of formula I or Ia can be chemically synthesized or isolated from natural sources, such as plants.

[0486] As further discussed in the examples, the synthesis of glycerols, glycolipids, lipids, etc., is well known, and those skilled in the art can readily prepare the compounds of the present invention by using and modifying known reaction mechanisms, as described in Manzo, E.; Letizia Ciavatta, M.; Pagaao, D.; Fontana, A. Tetrahedron Lett. 2012, 53,879. Additionally, some glycerols, glycolipids, lipids, etc., are naturally occurring and can therefore be isolated from plant materials such as tomatoes.

[0487] The present invention further provides a pharmaceutical composition comprising:

[0488] Compounds of formula I or Ia, or pharmaceutically acceptable salts thereof; and

[0489] - A pharmaceutically acceptable carrier, diluent, or excipient.

[0490] The carrier may be, for example, water or an aqueous fluid, such as saline solution. However, those skilled in the art will be fully aware that pharmaceutical carriers, diluents, or excipients are preferred.

[0491] The compound of formula I or Ia, or a pharmaceutically acceptable salt thereof, may be any of the definitions above.

[0492] The compound may optionally be according to any formula (Ib), (Ic), (Id), (Ie), II, III, IV, V, or VI. The compound may be selected from compounds 99, 218, 139, 184, 123, 180, 124, 159, 38, 215, 146, 122, 119, 62, 120, 46, 61, 57, 60, 56, 154, and 58 (e.g., ...). Figure 16Or as shown in 17) any of the compounds or mixtures thereof, or pharmaceutically acceptable salts thereof. For example, the compounds may be composed of compounds selected from compounds 99, 218, 139, 184, 123, 180, 124, 122, 119, 62, 120, and 46 (as shown in 17). Figure 16 Any one of the compounds or mixtures thereof, or a pharmaceutically acceptable salt thereof, from the group shown in the diagram.

[0493] The pharmaceutical composition may also contain, in addition to compounds of formula I or Ia, or pharmaceutically acceptable salts thereof, one or more other anticancer agents, such as chemotherapy agents.

[0494] The pharmaceutical composition may comprise (i) a compound selected from the group consisting of compounds 99, 218, 139, 184, 123, 180, 124, 38, 122, 119, 62, 120, 46, 61, 57, 60, 56, 154 and 58 and combinations thereof, and (ii) at least one further anticancer agent, such as a chemotherapy agent.

[0495] Alternatively, the pharmaceutical composition may contain (i) a compound selected from the group consisting of compounds 99, 218, 139, 184, 123, 180, 124, 38, 122, 119, 62, 120 and 46 and combinations thereof, and (ii) at least one further anticancer agent, such as a chemotherapy agent.

[0496] Alternatively, the pharmaceutical composition may comprise (i) compounds of the group consisting of compounds 61, 57, 60, 56, 154 and 58 and combinations thereof, and (ii) at least one further anticancer agent, such as a chemotherapy agent.

[0497] The anticancer drug, such as a chemotherapy agent, may contain cis-diamine dichloroplatin(ii) (cisplatin). TM Doxorubicin (7S,9S)-7-[(2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyloxane-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7H-tetraphenyl-5,12-dione) TM (or any other chemotherapy reagent)

[0498] The present invention may, in another aspect, provide compounds of formula I or Ia suitable as protein translation inhibitors, or pharmaceutically acceptable salts thereof. More preferably, the compounds of the present invention can inhibit protein translation by inhibiting eukaryotic ribosome activity, particularly ribosome recruitment. The compounds can selectively inhibit eIF4A-dependent or independent translation.

[0499] The compound of formula I or Ia, or a pharmaceutically acceptable salt thereof, may be any of the definitions given above.

[0500] The compound may optionally be formulated according to any of the formulas (Ib), (Ic), (Id), (Ie), II, III, IV, V, or VI. The compound may be selected from compounds 99, 218, 139, 184, 123, 180, 124, 159, 38, 215, 146, 122, 119, 62, 120, 46, 61, 57, 60, 56, 154, and 58 (e.g., ...). Figure 16 Or as shown in 17) any of the compounds or mixtures thereof, or pharmaceutically acceptable salts thereof. For example, the compounds may be composed of compounds selected from compounds 99, 218, 139, 184, 123, 180, 124, 122, 119, 62, 120 and 46 (as shown in 17). Figure 16 The compounds or mixtures thereof in the group shown, or pharmaceutically acceptable salts thereof.

[0501] The compounds of the present invention can inhibit protein translation by selectively reducing the translation of mRNAs with long-structured UTrs.

[0502] According to a further aspect, the present invention provides a protein translation inhibitor containing the compound of formula I or Ia or a pharmaceutically acceptable salt thereof, for example, the compound of formula II.

[0503] The compound of formula I or Ia, or a pharmaceutically acceptable salt thereof, may be any of the definitions given above.

[0504] The compound may optionally be according to any formula (Ib), (Ic), (Id), (Ie), II, III, IV, V, or VI. The compound may be selected from compounds 99, 218, 139, 184, 123, 180, 124, 159, 38, 215, 146, 122, 119, 62, 120, 46, 61, 57, 60, 56, 154, and 58 (e.g., ...). Figure 16 Or as shown in 17) any of the compounds or mixtures thereof, or pharmaceutically acceptable salts thereof. For example, the compounds may be composed of compounds selected from compounds 99, 218, 139, 184, 123, 180, 124, 122, 119, 62, 120 and 46 (as shown in 17). Figure 16 The compounds or mixtures thereof in the group shown, or pharmaceutically acceptable salts thereof.

[0505] According to a further aspect, the present invention provides a compound of formula I or Ia suitable as a protein translation inhibitor, or a pharmaceutically acceptable salt thereof, for example, the compound of formula II.

[0506] The compound of formula I or Ia, or a pharmaceutically acceptable salt thereof, may be any of the definitions given above.

[0507] The compound may optionally be according to any formula (Ib), (Ic), (Id), (Ie), II, III, IV, V, or VI. The compound may be selected from compounds 99, 218, 139, 184, 123, 180, 124, 159, 38, 215, 146, 122, 119, 62, 120, 46, 61, 57, 60, 56, 154, and 58 (e.g., ...). Figure 16 Or as shown in 17) any of the compounds or mixtures thereof, or pharmaceutically acceptable salts thereof. For example, the compounds may be composed of compounds selected from compounds 99, 218, 139, 184, 123, 180, 124, 122, 119, 62, 120 and 46 (as shown in 17). Figure 16 The compounds or mixtures thereof in the group shown, or pharmaceutically acceptable salts thereof.

[0508] According to further aspects, the present invention provides adjuvants and / or chemotherapeutic agents and / or antiproliferative agents and / or antiviral agents and / or cell sensitizers comprising compounds of formula I or Ia, or pharmaceutically acceptable salts thereof, such as compounds of formula II, suitable as adjuvants, chemotherapeutic agents, antiproliferative agents, antiviral agents, and cell sensitizers.

[0509] The compound of formula I or Ia, or a pharmaceutically acceptable salt thereof, may be any of the definitions given above.

[0510] The compound may optionally be according to any formula (Ib), (Ic), (Id), (Ie), II, III, IV, V, or VI. The compound may be selected from compounds 99, 218, 139, 184, 123, 180, 124, 159, 38, 215, 146, 122, 119, 62, 120, 46, 61, 57, 60, 56, 154, and 58 (e.g., ...). Figure 16 The compounds may consist of any one of the compounds or mixtures thereof from the group consisting of compounds 99, 218, 139, 184, 123, 180, 124, 122, 119, 62, 120 and 46 (as shown in 17). For example, the compounds may consist of compounds selected from compounds 99, 218, 139, 184, 123, 180, 124, 122, 119, 62, 120 and 46 (as shown in 17). Figure 16The compounds of the group shown in the figure, or mixtures thereof, or pharmaceutically acceptable salts thereof.

[0511] In embodiments or aspects of the present invention relating to antiviral compounds or methods suitable for the prevention or treatment of viral infections, the virus may be selected from any virus in the group consisting of herpes simplex virus (HSV); HIV; influenza virus; coronavirus; rhinovirus; and human cytomegalovirus (HCMV); or combinations thereof.

[0512] In a further alternative aspect, the present invention provides compounds of formula I or Ia, or pharmaceutically acceptable salts thereof, suitable for treating diseases or conditions selected from the group consisting of cancer, Alzheimer's disease, Parkinson's disease, Huntington's disease, muscular dystrophy, and autism spectrum disorder. Preferably, compounds of formula I or Ia, or pharmaceutically acceptable salts thereof, are suitable for treating cancer.

[0513] The compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, can be any of the definitions given above.

[0514] The compound may optionally be according to any formula (Ib), (Ic), (Id), (Ie), II, III, IV, V, or VI. The compound may be selected from compounds 99, 218, 139, 184, 123, 180, 124, 159, 38, 215, 146, 122, 119, 62, 120, 46, 61, 57, 60, 56, 154, and 58 (e.g., ...). Figure 16 Or as shown in 17) any of the compounds or mixtures thereof, or pharmaceutically acceptable salts thereof. For example, the compounds may be composed of compounds selected from compounds 99, 218, 139, 184, 123, 180, 124, 122, 119, 62, 120 and 46 (as shown in 17). Figure 16 The compounds of the group shown in the figure, or mixtures thereof, or pharmaceutically acceptable salts thereof.

[0515] The cancer can be selected from malignant epithelial tumors (carcinoma), lymphoma, blastoma, sarcoma, and leukemia. More specifically, examples of such cancers include squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, peritoneal cancer, hepatocellular carcinoma, gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatocellular carcinoma, breast cancer, colon cancer, colorectal cancer, endometrial cancer or cervical cancer, salivary gland cancer, kidney cancer, liver cancer, prostate cancer, vulvar cancer, thyroid cancer, stomach cancer, melanoma, and various types of head and neck cancers. The cancer can be selected from breast, lung, or ovarian cancer.

[0516] In a further alternative aspect, the present invention provides compounds of formula I or Ia, or pharmaceutically acceptable salts thereof, suitable for treating diseases or conditions caused by protein translation disorders.

[0517] The compound of formula I or Ia, or a pharmaceutically acceptable salt thereof, may be any of the definitions given above.

[0518] The compound may optionally be according to any formula (Ib), (Ic), (Id), (Ie), II, III, IV, V, or VI. The compound may be selected from compounds 99, 218, 139, 184, 123, 180, 124, 159, 38, 215, 146, 122, 119, 62, 120, 46, 61, 57, 60, 56, 154, and 58 (e.g., ...). Figure 16 The compounds may be any one of the compounds or mixtures thereof from the group consisting of (or shown in 17), or pharmaceutically acceptable salts thereof. For example, the compounds may be selected from compounds 99, 218, 139, 184, 123, 180, 124, 122, 119, 62, 120, and 46 (as shown in 17). Figure 16 The compounds or mixtures thereof in the group shown, or pharmaceutically acceptable salts thereof.

[0519] The disease or condition can be selected from the group consisting of cancer, Alzheimer's disease, Parkinson's disease, Huntington's disease, muscular dystrophy, and autism spectrum disorder. The disease or condition can be selected from the group consisting of cancer, Alzheimer's disease, and autism spectrum disorder. The disease or condition can be cancer.

[0520] Cell sensitizers can exert their effects by being administered concurrently with or following treatment with another active agent, thereby sensitizing cells. For example, sensitized cells can enhance the sensitivity of cells to anticancer drugs, such as chemotherapy agents, making the anticancer drugs more effective or effective at lower doses.

[0521] The compounds of formula I or Ia, or their pharmaceutically acceptable salts, may have additional therapeutic effects when administered in combination with anticancer drugs, such as chemotherapeutic agents.

[0522] The compound selected from any one of compounds comprising compounds 99, 218, 139, 184, 123, 180, 124, 38, 122, 119, 62, 120, 46, 61, 57, 60, 56, 154 and 58, or combinations thereof, or any pharmaceutically acceptable salts thereof, may be used in combination with at least one further anticancer agent such as a chemotherapy agent.

[0523] A compound selected from any one of the groups comprising compounds 99, 218, 139, 184, 123, 180, 124, 159, 38, 122, 119, 62, 120 and 46, or combinations thereof, or pharmaceutically acceptable salts thereof, may be used in combination with at least one further anticancer agent, such as a chemotherapy agent.

[0524] A compound selected from any one of compounds comprising compounds 61, 57, 60, 56, 154 and 58, or combinations thereof, or pharmaceutically acceptable salts thereof, may be used in combination with at least one further anticancer agent such as a chemotherapy agent.

[0525] In another aspect, the present invention provides a compound of formula I or Ia or a pharmaceutically acceptable salt thereof suitable for treating a disease or condition, wherein the compound of formula I or Ia or a pharmaceutically acceptable salt thereof is administered as a first therapeutic agent and other therapeutic agents are administered as a second therapeutic agent, wherein the dose of the second therapeutic agent, preferably the daily dose, is significantly reduced (e.g., reduced by 10% or more, or 20% or more, or 30% or more) compared to the daily dose when the second therapeutic agent is administered alone.

[0526] The compounds of formula I or Ia, or pharmaceutically acceptable salts thereof, may be used according to any of the definitions given above.

[0527] The compound may optionally be according to any formula (Ib), (Ic), (Id), (Ie), II, III, IV, V, or VI. The compound may be selected from compounds 99, 218, 139, 184, 123, 180, 124, 159, 38, 215, 146, 122, 119, 62, 120, 46, 61, 57, 60, 56, 154, and 58 (e.g., ...). Figure 16 The compounds may be any one of the compounds in group 17 or shown, or a mixture thereof, or a pharmaceutically acceptable salt thereof. For example, the compounds may comprise compounds 99, 218, 139, 184, 123, 180, 124, 122, 119, 62, 120, and 46 (as shown in Figure 17). Figure 16 The compounds or mixtures thereof in the group shown, or pharmaceutically acceptable salts thereof.

[0528] The first therapeutic agent may contain a compound selected from any one of the compounds comprising compounds 99, 218, 139, 184, 123, 180, 124, 38, 122, 119, 62, 120, 46, 61, 57, 60, 56, 154 and 58, or a combination thereof or a pharmaceutically acceptable salt thereof.

[0529] Alternatively, the first therapeutic agent may contain a compound selected from any one of the compounds comprising compounds 99, 218, 139, 184, 123, 180, 124, 159, 38, 122, 119, 62, 120 and 46, or a combination thereof or a pharmaceutically acceptable salt thereof.

[0530] Alternatively, the first therapeutic agent may contain a compound selected from any one of the compounds comprising compounds 61, 57, 60, 56, 154 and 58, or a combination thereof or a pharmaceutically acceptable salt thereof.

[0531] The first and second therapeutic agents are preferably suitable for treating cancer; the first therapeutic agent may be a cell sensitizer that sensitizes cells to the effects of the second therapeutic agent. The second therapeutic agent is preferably an anticancer drug, preferably a chemotherapeutic agent. The first and second therapeutic agents may be administered simultaneously, sequentially, or independently. By administering a compound of formula I or Ia, the dose of the anticancer drug (specifically a chemotherapeutic agent) used to effectively combat a specific cancer can be reduced by about 5 to about 100 times. The daily dose of the chemotherapeutic agent can be reduced by about 5 to about 100 times, preferably at least about 5 times, more preferably about 5 to about 50 times, or about 5 to about 40 times, or about 20 to about 50 times, or about 20 to about 40 times, or about 40 times.

[0532] In another aspect, the present invention provides a method for reducing the required dosage of an anticancer drug, the method comprising administering to a subject with cancer or cancer cells a measured amount of a compound of formula I or Ia, or a pharmaceutically acceptable salt thereof, which effectively sensitizes cancer cells to an anticancer drug. The anticancer drug may be a chemotherapeutic agent.

[0533] The compound of formula I or Ia, or a pharmaceutically acceptable salt thereof, may be any of the definitions given above.

[0534] The compound may optionally be according to any formula (Ib), (Ic), (Id), (Ie), II, III, IV, V, or VI. The compound may be selected from compounds 99, 218, 139, 184, 123, 180, 124, 159, 38, 215, 146, 122, 119, 62, 120, 46, 61, 57, 60, 56, 154, and 58 (e.g., ...). Figure 16 Or as shown in 17) any compound, or a mixture thereof, or a pharmaceutically acceptable salt thereof. For example, the compound may be composed of a compound selected from compounds 99, 218, 139, 184, 123, 180, 124, 122, 119, 62, 120 and 46 (as shown in 17). Figure 16 The compounds or mixtures thereof in the group shown, or pharmaceutically acceptable salts thereof.

[0535] In a further aspect, the present invention provides a method for enhancing the therapeutic activity of an anticancer drug, comprising administering to a patient a measured amount of a compound of formula I or Ia, or a pharmaceutically acceptable salt thereof, which effectively sensitizes cancer cells in the patient to the anticancer drug. The compound of formula I or Ia may be administered simultaneously, sequentially, or independently of the anticancer drug.

[0536] The compound of Formula 1 or Ia, or a pharmaceutically acceptable salt thereof, may be any of the definitions given above.

[0537] The compound may optionally be according to any formula (Ib), (Ic), (Id), (Ie), II, III, IV, V, or VI. The compound may be selected from compounds 99, 218, 139, 184, 123, 180, 124, 159, 38, 215, 146, 122, 119, 62, 120, 46, 61, 57, 60, 56, 154, and 58 (e.g., ...). Figure 16 Or as shown in 17) any of the compounds or mixtures thereof, or pharmaceutically acceptable salts thereof. For example, the compounds may be composed of compounds selected from compounds 99, 218, 139, 184, 123, 180, 124, 122, 119, 62, 120 and 46 (as shown in 17). Figure 16 The compounds or mixtures thereof in the group shown, or pharmaceutically acceptable salts thereof.

[0538] The compounds of formula I or Ia can be used to induce cell reactivity, such as cancer cells, to known chemotherapeutic agents, for example, cis-diamine dichloroplatin(II) (cisplatin) TM Doxorubicin (7S,9S)-7-[2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyloxane-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7H-tetraphenyl-5,12-dione) TM ), or any other chemotherapy reagent for sensitization.

[0539] Chemotherapy agents are chemical compounds used to treat cancer. Examples of chemotherapy agents include chemical compounds used to treat cancer. Examples of chemotherapy agents include alkylating agents, such as thiotepa and... Cyclophosphamide; alkyl sulfonates, such as busulfan, improsulfan, and piposulfan; aziridines, such as benzodepa, carboquone, meturedopa, and uredopa; ethyleneimines and methylamelamines, including etherretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolomelamine; acetone lactones (Ac... etogenin (especially bullatacin and bullatacinone); camptothecin (including synthetic analogs topotecan); bryostatin; callystatin; CC-1065 (including other synthetic analogs adozellesin, carzelesin, and bizelesin); cryptophycins (especially novophycin 1 and novophycin 8); dolastatin; duocarmycin (including synthetic analogs, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; sarcodictyin; spongistatin;Nitrogen mustards, such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxychloride hydrochloride, melphalan, Novembichin, phenesterine, prednimustine, trofosfamide, and uracil. Mustard; Nitrosoureas, such as carmustine, chlorpromazine, fotemustine, lomustine, nimustine, and ranimustine; Antibiotics, such as enediyne antibiotics (e.g., calichimycin, especially calichimycin γ11 and calichimycin ω11 (see, e.g., Nicolaou et al, Angew. Chem. Inti.Ed.Engl.,33:183-186(1994)); danemicins, including danemicin A; bisphosphonates, such as clodronate; esperamicin; and neocarzinostatin chromophores and related chromogenic chromophores of ethynylene antibiotics, aclacinomysin, actinomycin, arbutin mycin, azaserine, bleomycin, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diaza-5-oxo-L-leucine, ADRIAM; Doxorubicin (including morpholine doxorubicin, cyanomorpholine doxorubicin, 2-pyrrole doxorubicin, and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, macrellomycin, mitomycins such as mitomycin C, and mycophenolic acid. Acids, nogalamycin, olivomycin, peplomycin, potfiromycin, puromycin, quelamycin, rodoubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites, such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs, such as denopterin, methotrexate, and pteroyltriglutamate. Trimetrexate; purine analogs, such as fludarabine, mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogs, such as ancitabine, azacitidine, 6-azouridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enoxatabine, and floxuridine; and androgens, such as calotestosterone and dromostanolone. Propionate, Epitiostanol, Mepitiostane, Testolactone; anti-adrenergic drugs such as Aminoglutethimide, Mitotane, Trilostane; folic acid supplements such as Folinic Acid; Aceglatone; Aldophosphamide Glycoside;Aminolevulinic acid; Eniluracil; Amsacrine; Bestrabucil; Bisantrene; Edatraxate; Defosfamine; Demecolcine; Diaziquone; Elfornithine; Elliptinium Acetate; Epothilone; Etoglucid; Gallium nitrate; Hydroxyurea; Lentinan; Lonidainine; Maytansinoids, such as Maytansine and Ansamitocin; Mitoguazone; Mitoxantrone; Mopidanmol; Nitraerine; Pentostatin; Phenamet; Pirarubicin; Losoxantrone; Podophylloxacin; 2-Ethylhydrazide; Procarbazine; Polysaccharide complex (JHS Natural Products, Eugene, OR); Razoxane; Rhizoxin; Sizofiran; Spirogermanium; Tenuzonic acid Acid); Triaziquone; 2,2',2"-Trichlorotriethylamine; Trichothecenes (especially T-2 toxin, Veracurin A, Roridin A, and Anguidine); Urethan; Vindesine; Dacarbazine; Mannomustine; Mitobronitol; Mitolactol; Pipobroman; Gacytosine; Arabinoside (“Ara-C”); Cyclophosphamide; Thiotepa; Taxoids, such as Paclitaxel (Bristol-Myers Squibb) Oncology, Princeton, NJ), Palitaxil's Cremophor-free, albumin-engineered nanoparticle formulation (American Pharmaceutical Partners, Schaumberg, Illinois) and Docetaxel (Rhone-Poulenc Rorer, Antony, France); Chloranbucil; Gemcitabine; Thioguanine; Mercaptopurine; Methotrexate; Platinum analogs, such as Cisplatin, Oxaliplatin, and Carboplatin; Vinblastine; Platinum; Etoposide (VP-16); Ifosfamide; Mitoxantrone; Vincristine; Vindesine Vinorelbine; Novantrone; Teniposide; Edartrexate; Daunomycin; Aminopterin; Xeloda (capecitabine); Ibandronate; Irinotecan (Camplosar. CPT-11) (including irinotecan with 5-FU and leucovorin); topoisomerase inhibitor FS2000; Difluoromethylornithine (DMFO); Retinoids, such as retinoic acid. (acid); capecitabine; cobretastatin; leucovorin (LV); oxaliplatin, including the oxaliplatin treatment regimen (FOLFOX); inhibitors of PKC-α, Raf, H-Ras, and EGFR (e.g., erlotinib). And VEGF-A that reduces cell proliferation, as well as any pharmaceutically acceptable salts, acids, or derivatives thereof. Also included, as defined herein, are anti-hormonal agents used to modulate or inhibit the hormonal effects on tumors, such as anti-estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including...). Tamoxifen, raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY1 17018, onapristone, and FARESTON-toremifene; aromatase inhibitors that regulate estrogen production in the adrenal glands and inhibit aromatase, such as, for example, 4(5)-imidazole, aminoglutethimide, Megestrol acetate, Exemestane, Formestanie, Fadrozole vorozole Letrozole and Anastrozole; and antiandrogens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; as well as troxacitabine (a 1,3-dioxane cytosine analog); antisense oligonucleotides, especially those that inhibit gene expression in signaling pathways involved in abnormal cell proliferation, such as, for example, PKC-α, Ralf, and H-Ras; ribozymes, such as VEGF expression inhibitors (e.g., (ribozymes) and HER2 expression inhibitors; vaccines, such as gene therapy vaccines, for example, vaccine, Vaccines and vaccine; rIL-2; Topoisomerase 1 inhibitors; rmRH; and any of the above pharmaceutically acceptable salts, acids, or derivatives.

[0540] In one embodiment, the second therapeutic agent is cis-diaminodichloroplatin(II) (cisplatin) TM (7S,9S)-7-[(2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyloxane-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7H-tetraphenyl-5,12-dione (doxorubicin) TM (or any other chemotherapy reagent)

[0541] The therapeutic dose of the compound of formula I or Ia or its salt may be varied depending on the type and severity of the disease or condition to be treated.

[0542] For example, in the treatment of cancer, when a compound of formula I or Ia or a salt thereof is used as a chemotherapeutic agent, the dosage used may be from about 30 mg to about 1200 mg per day. The compound of formula I or Ia or a salt thereof may be administered in single or multiple doses. The multiple doses may be administered over a day or over several days, for example, over two or three days, or over four or five days or longer. The daily dose may be from 60 to 300 mg per 70 kg of subject weight.

[0543] For example, for the treatment of Alzheimer's disease, Parkinson's disease, Huntington's disease, muscular dystrophy, viral infections, or autism spectrum disorder, the dosage of Formula I or Ia or its salts may be from about 3 mg to about 120 mg / day. The compounds of Formula I or Ia or their salts may be administered in single or multiple doses, which may be administered over a day or over several days, for example, over 2 or 3 days, or over 4 or 5 days or longer. The daily dose may be 6 to 30 mg / 70 kg of subject body weight.

[0544] For example, in the treatment of cancer, when the compound of formula I or Ia or its salt is used to sensitize cancer cells to different chemotherapeutic agents, the dosage used may be from about 3 mg to about 1200 mg per day. The compound of formula I or Ia or its salt may be administered in single or multiple doses. The multiple doses may be administered over a day or over several days, for example, over 2 or 3 days, or over 4 or 5 days or longer. The daily dose may be 60 to 300 mg / 70 kg of subject weight. The daily dose may be 10 to 70 mg / 70 kg of subject weight. This allows for a reduction of at least about 5 times in the dosage of chemotherapeutic agents compared to the recommended dosage when the compound of formula I or Ia or its salt is not present. The daily dose of the chemotherapeutic agent may be reduced by about 5 to about 100 times, preferably at least about 5 times, more preferably about 5 to about 50 times, or about 5 to about 40 times, or about 20 to about 50 times, or about 20 to about 40 times, or about 40 times.

[0545] According to a further aspect, the present invention provides a method for inhibiting protein translation, comprising administering to cells or a subject a composition according to the invention or a compound of formula I or Ia or a pharmaceutically acceptable salt thereof.

[0546] The compound of formula I or Ia, or a pharmaceutically acceptable salt thereof, may be any of the definitions given above.

[0547] The compound may optionally be formulated according to any of the formulas (Ib), (Ic), (Id), (Ie), II, III, IV, V, or VI. The compound may be composed of compounds selected from compounds 99, 218, 139, 184, 123, 180, 124, 159, 38, 215, 146, 122, 119, 62, 120, 46, 61, 57, 60, 56, 154, and 58 (e.g., ...). Figure 16 Or as shown in 17) any of the compounds or mixtures thereof from the group consisting of, or pharmaceutically acceptable salts thereof. For example, the compounds may be composed of compounds selected from compounds 99, 218, 139, 184, 123, 180, 124, 122, 119, 62, 120 and 46 (as shown in 17). Figure 16The compounds of the group shown in the figure, or mixtures thereof, or pharmaceutically acceptable salts thereof.

[0548] According to another aspect, the present invention provides a method for treating a disease or condition in a subject who requires treatment, such as cancer, Alzheimer's disease, Parkinson's disease, Huntington's disease, muscular dystrophy, and autism spectrum disorder, comprising administering to the subject a therapeutically effective amount of a compound of formula I or Ia or a pharmaceutically acceptable salt thereof.

[0549] The compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, can be any of the definitions given above.

[0550] The compound may optionally be formulated according to any of the formulas (Ib), (Ic), (Id), (Ie), II, III, IV, V, or VI. The compound may be selected from compounds 99, 218, 139, 184, 123, 180, 124, 159, 38, 215, 146, 122, 119, 62, 120, 46, 61, 57, 60, 56, 154, and 58 (e.g., ...). Figure 16 Or as shown in 17) any of the compounds or mixtures thereof, or pharmaceutically acceptable salts thereof. For example, the compounds may be composed of compounds selected from compounds 99, 218, 139, 184, 123, 180, 124, 122, 119, 62, 120 and 46 (as shown in 17). Figure 16 The compounds or mixtures thereof in the group shown, or pharmaceutically acceptable salts thereof.

[0551] The compounds of formula I or Ia, or salts thereof, may be administered alone or in combination with another active agent. For example, to treat cancer, the compounds of formula I or Ia, or salts thereof, may be administered in combination with a chemotherapeutic agent. Administration of the compounds of formula I or Ia, or salts thereof, may mean that the chemotherapeutic agent is more effective or efficient at a lower dose.

[0552] In one embodiment, compounds 99, 218, 139, 184, 123, 180, 124, 159, 38, 215, 146, 122, 119, 62, 120, or 46 are administered alone.

[0553] In one embodiment, compounds 61, 57, 60, 56, 154, or 58 are administered in combination with another active agent. In another embodiment, compounds 99, 218, 139, 184, 123, 180, 124, 38, 122, 119, 62, 120, 46, 61, 57, 60, 56, 154, or 58 are administered in combination with another active agent.

[0554] The compounds or compositions according to the present invention can act as antiproliferative agents that slow down the proliferation of cells, specifically cancer cells.

[0555] According to another aspect, the present invention provides the use of a compound of formula I or Ia, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating a disease or condition caused by protein translational disorders.

[0556] The compound of formula I or Ia, or a pharmaceutically acceptable salt thereof, may be any of the definitions given above.

[0557] The compound may optionally be formulated according to any of the formulas (Ib), (Ic), (Id), (Ie), II, III, IV, V, or VI. The compound may be selected from compounds 99, 218, 139, 184, 123, 180, 124, 159, 38, 215, 146, 122, 119, 62, 120, 46, 61, 57, 60, 56, 154, and 58 (e.g., ...). Figure 16 Or as shown in 17) any of the compounds or mixtures thereof, or pharmaceutically acceptable salts thereof. For example, the compounds may be composed of compounds selected from compounds 99, 218, 139, 184, 123, 180, 124, 122, 119, 62, 120 and 46 (as shown in 17). Figure 16 The compounds or mixtures thereof in the group shown, or pharmaceutically acceptable salts thereof.

[0558] In a further aspect, the present invention provides the use of a compound of formula I or Ia, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating a disease or condition selected from the group consisting of cancer, Alzheimer's disease, Parkinson's disease, Huntington's disease, muscular dystrophy, viral infection, and autism spectrum disorder. Preferably, the medicament is suitable for treating cancer.

[0559] The compound of formula I or Ia, or a pharmaceutically acceptable salt thereof, may be any of the definitions given above.

[0560] The compound may optionally be formulated according to any of the formulas (Ib), (Ic), (Id), (Ie), II, III, IV, V, or VI. The compound may be selected from compounds 99, 218, 139, 184, 123, 180, 124, 159, 38, 215, 146, 122, 119, 62, 120, 46, 61, 57, 60, 56, 154, and 58 (e.g., ...). Figure 16Or as shown in 17) any of the compounds or mixtures thereof, or pharmaceutically acceptable salts thereof. For example, the compounds may be composed of compounds selected from compounds 99, 218, 139, 184, 123, 180, 124, 122, 119, 62, 120 and 46 (as shown in 17). Figure 16 The compounds of the group shown in the figure, or mixtures thereof, or pharmaceutically acceptable salts thereof.

[0561] The present invention can further provide products comprising at least one compound of formula I or Ia or a pharmaceutically acceptable salt thereof and a chemotherapeutic agent as a combination formulation for simultaneous, independent, or sequential use in anticancer therapy. The compound of formula I or Ia or a salt thereof and the chemotherapeutic agent may be provided in the same or different formulations.

[0562] The compounds of formula I or Ia, or pharmaceutically acceptable salts thereof, may be used according to any of the definitions given above.

[0563] The compound may optionally be formulated according to any of the formulas (Ib), (Ic), (Id), (Ie), II, III, IV, V, or VI. The compound may be selected from compounds 99, 218, 139, 184, 123, 180, 124, 159, 38, 215, 146, 122, 119, 62, 120, 46, 61, 57, 60, 56, 154, and 58 (e.g., ...). Figure 16 The compound may consist of any one of the compounds or mixtures thereof, or pharmaceutically acceptable salts thereof, from the group consisting of compounds 99, 218, 139, 184, 123, 180, 124, 122, 119, 62, 120, and 46 (as shown in 17). Compounds of formula I inhibit protein synthesis Any compound or mixture thereof, or a pharmaceutically acceptable salt thereof, from the group shown in the figure.

[0564] In another aspect, the present invention provides a kit containing a compound of formula I or Ia as a first therapeutic agent, or a pharmaceutically acceptable salt thereof, and an anticancer drug as a second therapeutic agent, wherein the anticancer drug is provided in a suitable manner and / or according to the instructions for daily administration, with a significantly reduced daily dose (e.g., a reduction of 10% or more, or 20% or more, or 30% or more) compared to the dose when the anticancer drug is administered alone. The first and second therapeutic agents may be intended to be administered simultaneously, sequentially, or independently. The anticancer drug may be a chemotherapeutic agent.

[0565] The compound of formula I or Ia, or a pharmaceutically acceptable salt thereof, may be any of the definitions given above.

[0566] The compound may optionally be formulated according to any of the formulas (Ib), (Ic), (Id), (Ie), II, III, IV, V, or VI. The compound may be selected from compounds 99, 218, 139, 184, 123, 180, 124, 159, 38, 215, 146, 122, 119, 62, 120, 46, 61, 57, 60, 56, 154, and 58 (e.g., ...). Figure 1 Or as shown in 17) any of the compounds or mixtures thereof, or pharmaceutically acceptable salts thereof. For example, the compounds may be composed of compounds selected from compounds 99, 218, 139, 184, 123, 180, 124, 122, 119, 62, 120 and 46 (as shown in 17). Figure 2 The compounds or mixtures thereof in the group shown, or pharmaceutically acceptable salts thereof.

[0567] Preferred formula I or Ia has no significant side effects when administered to the subject. Preferably, the compound is non-toxic to the subject at the dose required for the desired therapeutic effect.

[0568] The compounds of formula I or Ia of the present invention can be formulated as prodrugs or protected formulations. The compounds can be either prodrugs or protected forms of the compounds that release the compounds upon administration to a subject. For example, the compounds may carry a protecting group that is cleaved by hydrolysis in bodily fluids, such as in the bloodstream, thereby releasing the active compound, or is released by oxidation or reduction in bodily fluids. The term "prodrug" contemplated refers to a compound that can be converted into the bioactive compounds of the present invention under physiological conditions or by solvent decomposition. Therefore, the term "prodrug" refers to a pharmaceutically metabolizable precursor of the compounds of the present invention. When administered to a subject in need, the prodrug may be inactive but is converted in vivo into the active compounds of the present invention. Prodrugs typically, for example, are rapidly converted in vivo through hydrolysis in the blood to produce the parent compounds of the present invention. The prodrug compounds typically provide advantages in the subject such as solubility, tissue compatibility, or delayed release.

[0569] The term "prodrug" can include any covalently bonded carrier that, when administered to a subject, releases the active compound of the present invention in vivo. Prodrug formulations of the compounds of the present invention can be prepared by modifying functional groups present in the compounds of the present invention in a manner that follows conventional procedures or decomposes in vivo into the parent compound of the present invention. Prodrugs include compounds of the present invention in which, when administered to a mammalian subject, the hydroxyl, amino, or thiol group is bonded to any group that cleaves to form a free hydroxyl, free amino, or free thiol group, respectively. Examples of prodrugs include, but are not limited to, acetates, formates, and formate derivatives of alcohols and acetamide, formamide, and benzamide derivatives with amino functional groups, etc.

[0570] For a discussion of prodrugs, see “Smith and Williams’ Introduction to the Principles of Drug Design,” H.S. Smith, Wright, 2nd ed., London (1988); its entire contents are incorporated herein by reference.

[0571] The compositions or compounds according to the invention, or the uses according to the invention, can be provided alone or in combination with other compounds, for example, in the presence of liposomes, adjuvants, or any pharmaceutically acceptable carrier, diluent, or excipient, in a form suitable for administration to a subject such as a mammal, e.g., a human, a cow, a sheep, etc. If desired, treatment with the compounds according to the invention can be combined with more conventional and existing therapies as described herein. For example, the compositions for treating cancer according to the invention can be administered in combination with one or more other anticancer therapies. Examples of anticancer therapies include, but are not limited to, surgery, radiation therapy (radiotherapy), biotherapy, immunotherapy, chemotherapy, or combinations thereof. Chemotherapy may include administration of one or more chemotherapeutic agents. The compositions according to the invention and one or more other anticancer therapies, such as one or more chemotherapeutic agents, can be administered alone, sequentially, or simultaneously.

[0572] Combination administration of compounds of formula I or Ia or their salts with other anticancer therapies includes co-administration or simultaneous administration using individual formulations or single-drug formulations, and sequential administration in any order in which the two (or all) active agents exert their biological activity simultaneously but optionally for a period of time.

[0573] "Pharmaceutically acceptable carriers, diluents, or excipients" include, but are not limited to, any adjuvant, carrier, excipient, gliding agent, sweetener, diluent, preservative, dye / coloring agent, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier approved by the United States Food and Drug Administration or other government agencies for use in humans or domestic animals.

[0574] All compounds of the present invention can be administered in the form of pharmaceutically acceptable salts, in which case the pharmaceutical composition according to the invention may contain a salt of such a compound, preferably a physiologically acceptable salt known in the art. In some embodiments, the term "pharmaceutically acceptable salt," as used herein, refers to an active ingredient comprising a compound of formula I used in its salt form, specifically wherein the salt form imparts improved pharmacokinetic properties to the active ingredient compared to the free form of the active ingredient or other previously disclosed salt forms.

[0575] The term "pharmaceutically acceptable salt" encompasses all acceptable salts, including, but not limited to, acetates, lactobionates, benzenesulfonates, laurates, benzoates, malates, bicarbonates, maleates, bisulfates, mandelates, tartrates, methanesulfonates, borates, methyl bromide, bromide, methyl nitrite, calcium ethylenediaminetetraacetate, methyl sulfate, camsylale, mucate, carbonates, napsylate, hydrochlorides, nitrates, clavulanate, N-methylglucosamine, citrates, ammonium salts, dihydrochlorides, oleates, ethylenediaminetetraacetate, oxalates, and ethylenedisulfonates. Pamoate (embonate), etopoate, palmitate, ethanesulfonate, pantothenate, fumarate, phosphate / hydrogen phosphate, glucono-p-phosphate, polygalacturonate, gluconate, salicylate, glutamate, stearate, glycolyllarsanilate, sulfate, hexylresorcinol, subacelate, hydradamine, succinate, hydrobromide, tannate, hydrochloride, tartrate, hydroxynaphthylcarboxylate, theochlorate, iodide, toluenesulfonate, isothionate, triethyliodide, lactate, panoate, valerate, etc.

[0576] Pharmaceutically acceptable salts of the compounds described in this invention can be used to modify solubility or hydrolysis properties, or to produce sustained-release formulations. Furthermore, pharmaceutically acceptable salts of the compounds described in this invention can include those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, and zinc, and from bases such as ammonia, ethylenediamine, N-methylglutamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenylethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, and tetramethylammonium hydroxide.

[0577] Pharmaceutical formulations typically include one or more carriers acceptable for a mode of administration of said formulation, which can be administered by injection, inhalation, topical administration, irrigation, enteral administration, or other modes suitable for the selected treatment. Suitable carriers are those known in the art for these modes of administration.

[0578] Suitable pharmaceutical compositions can be formulated in a manner known in the art, and in a manner and dosage determined by a skilled physician. For parenteral administration, the compound can be dissolved in sterile water or saline, or in a pharmaceutically acceptable carrier for administering non-water-soluble compounds, such as those for vitamin K. For enteral administration, the compound can be administered in tablet, capsule, or liquid form. The tablet or capsule may be enteric-coated or used in a formulation for sustained release. Many suitable formulations are known, including polymer or protein microparticles encapsulating the compound to be released, ointments, gels, hydrogels, or solutions capable of delivering the compound topically or locally to the body. Sustained-release patches or implants over an extended period of time can be used to provide release. Many techniques known to those skilled in the art are described in Remington: the Science & Practice of Pharmacy, 20th edition, Williams & Wilkins, (2000), edited by Alfonso Gennaro. Formulations for parenteral administration may, for example, contain excipients, polyalkylene glycols such as polyethylene glycol, plant-derived oils, or hydrogenated naphthalene. Biocompatible, biodegradable lactide polymers, lactide / glycolic acid copolymers, or polyethylene glycol-polypropylene glycol copolymers can all be used to control the release of the compounds. Other potentially useful parenteral delivery systems for modulating compounds include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Formulations for inhalation may contain excipients such as lactose, or may be aqueous solutions containing, for example, polyethylene glycol-9-lauryl ether, glycocholate, and deoxycholate, or may be oily solutions for administration as nasal drops or as gels.

[0579] The compounds or pharmaceutical compositions according to the present invention can be administered orally or non-orally, for example, intramuscularly, intraperitoneally, intravenously, intracranially, subcutaneously, transdermally, or via mucosal routes. In some embodiments, the compounds or pharmaceutical compositions according to the present invention or applicable to the present invention can be administered via medical devices or appliances such as implants, grafts, prostheses, temporary catheters, etc. Implants designed to contain and release such compounds or compositions can be designed. One example would be an implant made of a polymeric material suitable for releasing the compound over a period of time. The compound can be administered alone or as a mixture with a pharmaceutically acceptable carrier, for example, as a solid dosage form, such as tablets, capsules, granules, powders, etc.; a liquid dosage form, such as syrups, injections, etc.; or as injections, drops, suppositories, vaginal suppositories. In some embodiments, compounds or pharmaceutical compositions according to or applicable to the invention may be administered via inhalation spray, nasal, vaginal, rectal, sublingual, or local routes, and may be formulated alone or together in appropriate dosage units containing conventional, non-toxic, pharmaceutically acceptable carriers, adjuvants, and carriers suitable for each route of administration.

[0580] The compounds of this invention can be used to treat animals, including mice, rats, horses, cattle, sheep, dogs, cats, and monkeys. The compounds of this invention can also be effectively used in humans. The term "subject" refers to an animal that has become a subject of treatment, observation, or experimentation, preferably a mammal, and most preferably a human. However, the compounds, methods, and pharmaceutical compositions of this invention can be used to treat animals. Therefore, as used herein, "subject" can be a human, a non-human primate, rat, mouse, cattle, horse, pig, sheep, goat, dog, cat, etc.

[0581] The "effective amount" of a compound according to the invention includes a therapeutically effective amount or a preventatively effective amount. A "therapeuticly effective amount" refers to the amount used to effectively achieve the desired therapeutic effect within the necessary dose and time period. The therapeutically effective amount of a compound can be varied based on factors such as the individual's disease state, age, sex, and weight, as well as the compound's ability to elicit the desired response in the individual. Dosing regimens can be adjusted to provide an optimal therapeutic response. The therapeutically effective amount is also the amount at which any toxic or adverse effect of the compound outweighs the beneficial therapeutic effect. A "preventatively effective amount" refers to the amount used to achieve the desired preventative effect within the necessary dose and time period. Typically, a preventative dose is administered to the subject before or in an early stage of the disease, so that the preventatively effective amount may be less than the therapeutically effective amount. Suitable ranges for the therapeutic or preventatively effective amounts of a compound can be any integer between 0.1 nM and 0.1 M, 0.1 nM and 0.05 M, 0.05 nM and 15 μM, or 0.01 nM and 10 μM.

[0582] The term "antiproliferator" refers to a pharmacological agent that blocks the growth of cells, parasites, or viruses.

[0583] The term "adjuvant" is intended to refer to a pharmacological agent that is added to, or administered together with, a drug or therapeutic agent to enhance or assist the effect of said drug or therapeutic agent.

[0584] Those skilled in the art should understand that all preferred or optional features of the present invention can be applied to all aspects of the present invention.

[0585] All references mentioned in this article are incorporated herein by reference.

[0586] result

[0587] Figure 3a

[0588] Polynucleotide profiling

[0589] By using polyribosomal profiling analysis (as illustrated by the compounds of Formula II in these experiments) Figure 3a Compounds of Formula I have been shown to be inhibitors of protein synthesis, as demonstrated by analysis of the number of mRNA-associated ribosomes in the presence and absence of said compounds. Figure 3b Standard sucrose density polyribosome profiling has demonstrated that treatment with compounds of Formula II reduces the average number of ribosomes per message in cultured human cells. The number of ribosomes indicates the translation of mRNA and the synthesis of proteins encoded by said mRNA, and treatment with the compounds of Formula II reduces the number of ribosomes per message, thereby reducing overall protein synthesis.

[0590] The use of the compound for inhibiting eIF4A

[0591] Reporter gene assays using a fully characterized luciferase base further confirmed that this type of molecule functions as a protein synthesis inhibitor by targeting the helicase eIF4A. Cricket paralysis virus RNA contains a well-documented internal ribosome entry site (CrPV IRES); this internal ribosome entry site does not require eIF4A for active translation (Bordeleau et al., 2006 Nature Chemical Biology, 2: 213-220). After treatment with the synthetic form of the natural molecule for 3 hours, cap-dependent (eIF4A-dependent) translation (firefly luciferase signaling) was inhibited, rather than CrPV iRES-dependent translation (Reniform luciferase signaling). Given the lack of detailed documentation regarding the eIF4A requirement for CrPV translation (e.g., Bordeleau et al., 2006 Nature Chemical Biology, 2: 213-220), this data further demonstrates that the inhibition is selective and provides evidence that the target is the translation initiation factor eIF4A.

[0592] Reporter gene analysis

[0593] Reporter gene analysis was used to demonstrate that the compound of Formula II is an inhibitor of protein synthesis. Firefly / Reniformis luciferase reporter gene assays were performed using cultured human cell lines, demonstrating that the compound of Formula II is a selective and facilitated inhibitor of protein synthesis (a schematic diagram of the reporter gene construct is included in...). Figure 3c , 3d (and 5). The compounds of Formula II have been shown to selectively reduce the levels of reporter gene constructs containing a long structured 5'UTR upstream of the firefly luciferase gene, but have little effect on co-transfected luciferase reporter gene constructs with a short, unstructured 5'UTR. Figure 3d and 5 ).

[0594] The degree of translational repression was equivalent to that of the known translation inhibitor polyhydroxynaphthene. Use of compounds of formula I in the treatment of cancer and 5 Controlled structuralized 5'UTR firefly luciferase reporter gene experiments using compound polyhydroxynaphthenic acid or compounds of formula II showed that the repression at the reporter gene level was equivalent. Using compounds of formula II and polyhydroxynaphthenic acid (… Figure 4a Co-treatment showed no additional inhibitory effect, providing further evidence that both molecules act on the same target, possibly the translation complex helicase protein eIF4A.

[0595] Firefly luciferase reporter gene assays using the 5'UTRs of genes negatively associated with disease demonstrated that by selectively altering the translation of selected copies while leaving the translation of housekeeping or protective genes unaffected, the inhibitory effect is both selective and relevant for the treatment of diseases such as Alzheimer's disease, cancer, and autism spectrum disorder. Figure 4a and 5 Following treatment with the compound of Formula II, the translation level of the reporter gene construct containing the 5'UTR (processed into amyloid protein, a major component of toxic amyloid plaques in Alzheimer's disease) was suppressed relative to the equivalent control treatment. Similar significant suppression was also observed after treatment of the construct containing the epidermal growth factor receptor (EGFR) gene in the 5'UTR (p = 0.005), whose expression and protein levels are negatively correlated with cancer progression and survival. These data also support a selective suppression model.

[0596] The data also support the use of compounds of Formula I for the treatment of diseases such as Alzheimer's disease, cancer, and autism spectrum disorder.

[0597] Figure 4c

[0598] Compounds of formula I or Ia, as exemplified by compounds of formula II, can be used alone to treat cancer, as demonstrated by their ability to act as antiproliferative agents when used as a standalone treatment. Figure 6 (b, c, 5, and 6). Since cancer cells recruit protein synthesis mechanisms that drive proliferation, this presents an attractive target for therapy. It has been well-demonstrated that rapidly growing tumor cell lines require relatively high levels of protein synthesis compared to normal cells—treatment of rapidly proliferating breast cancer cell lines (MCF-7 and MDA-MD-231) with the compounds of Formula II significantly limited the proliferation of these cell types. Figure 9a , 4b Treating slow-growing cell lines, such as SKOV3 ovarian cancer cells, with the compounds of Formula II is equivalent to treatment. Figure 6 It showed a certain degree of slowed proliferation.

[0599] Similar results were observed in A54 lung cancer cells. Figure 9a and Figure 4d For those from natural sources ( Figure 8 ) and compounds of formula II synthesized by chemical synthesis ( Figure 9b Similar results were observed for the compounds of Formula II during purification.

[0600] Compounds of Formula I or Ia, as exemplified by compounds of Formula II, can also be used in combination with other chemotherapeutic agents for treating cancer. Compounds of Formula I or Ia can sensitize cells to the chemotherapeutic agent, thereby reducing the required dose. This is particularly advantageous when the chemotherapeutic agent may be toxic and especially difficult for patients to tolerate. The side effects of chemotherapeutic agents at currently required doses are in some cases so severe that the use of potentially effective drugs is ruled out.

[0601] Known inhibitors of protein synthesis, such as polyhydroxynaphthene, have been shown to have potent anticancer properties when used in combination with chemotherapeutic agents such as cisplatin or doxorubicin. However, polyhydroxynaphthene, naturally found in corals, is scarce and expensive to obtain, and its synthesis is also very difficult and costly. The data presented in this article indicate that compounds of formula I or Ia, such as those of formula II, can be used as adjuvants in combination with chemotherapeutic agents to enhance cell death; specifically, this combination is potent in slowing proliferation or killing cancer cells. Slow-growing and difficult-to-treat tumor cell types, such as AS49 lung cancer cells, SH-SY5Y neuroblastoma, or SKOV-3 cancer cells, were all sensitized by exposure to very low doses of cisplatin of formula II. Figure 11 (4e, 4f, and 7) - Single-dose treatment with compounds of formula II in combination with 1 μM or 2.5 μM cisplatin at the μg level resulted in complete eradication in both A549 and SH-SY5Y cells. Similar effects were observed when compounds of formula II were used in conjunction with chemotherapeutic agents such as cisplatin in the treatment of rapidly growing tumor cell lines or primary tumor cells. Figure 9c In this embodiment, primary tumor cells were isolated from dogs and subsequently exposed in vitro to the compound of Formula II and cisplatin. The results showed that many cancer cells remained when treated with cisplatin alone; however, when treated with cisplatin and the compound of Formula II, virtually all tumor cells were killed. This is not visible in the images reproduced herein, but is visible under a microscope, showing that leukocytes that had metastasized with the tissue sample remained viable after treatment with the cisplatin and compound of Formula II. This demonstrates the adjuvant properties of the compound of Formula I, and more specifically, demonstrates that the compound of Formula I can sensitize cancer cells to the effects of chemotherapeutic agents.

[0602] Figure 13 The results indicate that chemically synthesized compounds of formula II are effective alone as anticancer drugs, and also as agents for sensitizing cancer cells to other chemotherapeutic agents. The previously discussed data were obtained using compounds of formula II isolated from tomatoes.

[0603] Figure 14The results shown demonstrate that treatment with the chemically synthesized compound of formula II exhibits a relative antiproliferative effect comparable to that with the known inhibitor polyhydroxynautiline. The relative activity as a sensitizing agent for cisplatin treatment is also equivalent at this dose.

[0604] Figure 5 The results indicate that the chemically synthesized acetyl derivatives of Formula II are also effective as sensitizers for cancer cells to other chemotherapeutic agents, specifically cisplatin in this particular embodiment. The acetyl derivatives of Formula II used in this study are shown below:

[0605]

[0606] Chemical formula: C 53 H 82 O 14 Molecular weight: 943.23.

[0607] Figure 10 It has been demonstrated that chemically synthesized derivatives of formula II (compounds 46, 99, and 123) are also effective as standalone anticancer drugs in a dose-dependent manner and can be used as agents to sensitize cancer cells to other chemotherapeutic agents. Figure 5 ).

[0608] The use of the compound in the treatment of autism.

[0609] Direct evidence was provided, based on data from Gkogkas et al. Nature 2013, 493:371-7, demonstrating that inhibiting eIF4A represents a novel approach to treating ASD. Firefly / Reniform luciferase reporter gene assays performed using cultured human cell lines showed that eIF4A is a viable therapeutic target for ASD, and that inhibition of eIF4A1 using any of the polyhydroxynaphthenic acid or synthetic versions and derivatives of the natural molecule (data also shown in 46) resulted in selective inhibition of NLGN1 translation.

[0610] Using the compounds of formula II (and compound 46) Figure 10 and Figure 1Treatment selectively reduced the firefly luciferase signal from a reporter gene construct containing the NLGN1 5'UTR upstream of the firefly luciferase gene. Translation of the luciferase reporter gene downstream of the NLGN1 5'UTR has been shown to depend on the activity of the translation initiation complex eIF4F (Gkogkas et al Nature 2013, 493:371-7) – this complex contains the helicase eIF4A. Equivalent treatment had little effect on the signal generated by co-transfected Renalis luciferase reporter gene controls or by cells transfected with an equivalent construct containing the NLGN2 5'UTR upstream of the firefly luciferase gene. Figure 16 and Figure 16 ).

[0611] The level of translational inhibition of NLGN1 was comparable to that induced by the known eIF4A inhibitor, polyhydroxynaphthene. This data further demonstrates that the compound targets the translation initiation complex when it exerts its effect and provides evidence that NLGN1 translation is relatively more dependent on eIF4A activity compared to NLGN2. The data also indicate that the observed inhibitory effect was not due to the antiproliferative activity of the compound at this dose and duration of treatment.

[0612] Materials and methods

[0613] Preparation of compounds of formula II

[0614] The compounds of Formula II are glycerol glycolipid lipids, the synthesis of which is well known. Those skilled in the art can readily prepare compounds of Formula II or their acetyl derivatives by following the reaction mechanisms described in the literature Manzo, E.; Letizia Ciavatta, M.; Pagano, D.; Fontaoa, A. Tetrahedron Lett. 2012, 53, 879.

[0615] Alternatively, the compound of Formula II can be recovered from plant material such as tomato. Tomatoes are grown under a standard glasshouse, harvested, and rapidly frozen in liquid nitrogen. The tissue is ground into powder under liquid nitrogen, mixed with 2 volumes of MeOH (wt / vol), and heated at 50°C for 10 minutes. The mixture is then centrifuged at 4000 rpm to obtain cell debris particles, and the supernatant is transferred to a clean tube. The MeOH is then partitioned into a chloroform phase, and the chloroform layer is subsequently dried to obtain the particles.

[0616] The crude extract was adsorbed onto chromatographic silica gel and dry-loaded onto a silica gel fast chromatography column. The product was eluted with a methanol gradient from 0% to 20% in dichloromethane, and each fraction was collected and its bioactivity was tested. The active fraction was vacuum evaporated to obtain an oil (155 mg). Further purification was performed by batch reversed-phase HPLC (Varian Prostar; Polaris 5 μm C18-A column (250 mm × 10 mm); gradient elution from 80% H2O 20% MeCN to 0% H2O 100% MeCN, following the procedure: 80% H2O 20% MeCN 2 min; 0% H2O 100% MeCN 20 min; 0% H2O 100% MeCN 48 min; 80% H2O 20% MeCN 50 min). The active fraction (eluted over 30 min) was collected and vacuum evaporated to obtain the active molecule, whose NMR ( 1 H and 13 C) HRMS and IR data confirm that it is... Figure 16 The structure shown.

[0617] Cell culture conditions

[0618] Cells were used and maintained under standard conditions, as described on the American Type Culture Collection web page (see ATCC, http: / / www.lgcsiaiidards--alcc.org), in suitable media supplemented with 10% FCS and 1% penicillin / streptomycin (Life Technologies), such as Dulbecco's Modified Eagle's Medium (DMEM) or Roswell Park Memorial Institute Medium (RPMI) (Sigma).

[0619] Polynucleotide profiling

[0620] Longitudinal images of polyribosomes were obtained using sucrose density centrifugation. Briefly, cultured neuroblastoma cells (SH-SY5Y) growing in one 15 cm well were treated each time until 70% confluence was achieved. Cells were then treated with an active or equivalent DMSO control for 20 min. Cells were harvested, lysed, and loaded onto a sucrose gradient, followed by centrifugation at 38,000 rpm for 2 h (as described in Bottley et al., 2010). The gradient was fractionated, and longitudinal images of polyribosomes were determined by continuous monitoring at 260 nm absorbance (previously described in Johannes et al., 1999).

[0621] Transient transfection conditions and luciferase reporter gene construct

[0622] Experiments were conducted using a firefly luciferase reporter gene plasmid containing the 5' untranslated region (UTR) of the genes amyloid precursor protein (APP) and thioredoxin (TXN), using reagents and materials as described in Bottley et al., 2010. Experiments were also conducted using a firefly luciferase reporter gene plasmid containing the 5' UTR of the genes EGFR, BACE1, and actin, using reagents and materials as described in Webb, 2012 (http: / / etheses.nottingham.ac.uk / 2724 / ). A firefly luciferase reporter gene plasmid containing the 5' UTR of the genes neuron 1 and neuron 2 was provided by Professor Nahum Sonenberg (McGill) and used according to the literature Gkogkas et al., Nature 2013, 493:371-7.

[0623] Cells were transfected using FuGene 6 (Roche) according to the manufacturer's instructions. The activities of firefly and kidney luciferase in lysates prepared from transfected cells were measured using a commercially available luciferase reporter assay system (Promega), and light emission was measured at 30-second intervals using a TECAN illuminometer. For each experiment described, data were obtained from at least three biological replicates for each treatment.

[0624] Cell proliferation experiment

[0625] Prior to treatment, cells were cultured in 96-well Fisher tissue culture plates to a suitable confluence. Cells were kept on fresh medium or treated with fresh medium containing the active compound or an equal volume of DMSO (carrier control). In the case of use, cisplatin was diluted to the stock concentration in dimethylformamide (DMF) and then treated according to the manufacturer's instructions. To determine relative cell viability, absorbance at 450 nm was measured using reagent WST-1 (Roche) or MTT (Sigma) according to the manufacturer's instructions and a Victor plate reader (Perkin Elmer).

[0626] Primary canine tumor cell experiments.

[0627] Biopsy tissue samples were taken from the knee, abdomen, and skin of 7-year-old dogs. Histological evaluation confirmed that the cells harvested from the canines were histiocytic sarcoma tumor cells. Samples were lysed at 37°C for 3 hours under controlled conditions before collagenase treatment. Cells were then pelleted by low-speed centrifugation and resuspended in selective culture medium using proprietary methods and materials developed by Petsereen Ltd. Experiments were performed in 96-well tissue culture plates, with at least three biological replicates for each treatment.

[0628] Figure 16 and 17 Preparation of compounds of Chinese formula I and Ia

[0629] Figure 16 and 17 The compounds of formula I and Ia are synthetic variants of the compounds of formula II. For example, they may use glucose or mannose units instead of galactose, and they may use central linker units with additional CH2 groups.

[0630] The synthesis of glycerol, glycolipids, and lipids is well-known, and technicians have been modifying them to prepare glycerol, glycolipids, and lipids. Figure 16 and 17 The compounds of formula I and Ia are within the capabilities of known reaction techniques (these compounds are 99, 218, 139, 184, 123, 180, 124, 159, 38, 215, 146, 122, 119, 62, 120, 46, 61, 57, 60, 56, 154 and 58, which are also shown in the above description).

[0631] Specifically, Figure 16 and 17Compounds of Chinese formula I and Ia were each prepared by following the reaction mechanism described in the literature Manzo, E.; Letizia Ciavatta, M.; Pagano, D.; Fontana, A. Tetrahedron Lett. 2012, 53, 879.

[0632] This synthesis is based on the trichloroacetylimine ester method and a general and simple approach using peracetic acid ester sugar substrates. The chemical strategy enables the stereoselective preparation of lipid derivatives of sugars such as galactose, glucose, and mannose, as well as other related derivatives. The synthetic method is designed to yield enantiomeric regio and stereoisomers, including derivatives containing polyunsaturated fatty acids.

[0633] Essentially, synthesis recognizes that glycerol, glycolipids, and lipids, such as:

[0634]

[0635] Able to be derived from the starting materials:

[0636]

[0637] The required changes to these starting materials to obtain Figure 16 and 17 The compounds in the compound can be readily identified by those skilled in the art; for example, different sugar units, linker units with additional CH2 groups, and the choice of R and R1 groups.

[0638] therefore, ​ and 17 The preparation of each compound is based on the following steps from that known synthetic route (illustrated below) and the selection of appropriate starting materials / reagents to provide suitable sugar units, R and R1 groups and linking units therebetween.

[0639]

[0640] ​ and 17 Most of the compounds prepared and illustrated in this paper are directly based on this synthetic method, with differences only in the choice of sugar, whether or not it is protected, and the choice of R and R′ groups. Examples include compounds 123, 180, 124, 38, 122, 119, 62, 120, 61, 57, 60, 56, and 58.

[0641] Synthetic route of compound 159

[0642] The synthetic route of 159 follows the same route used by all other esters mentioned in the aforementioned Tetrahedron Letters article by Manzo, E, et al., with the only difference being the use of phenylacetic acid instead of fatty acids to provide the R and R′ groups.

[0643] Synthetic route of compound 139

[0644]

[0645] Preparation of ketone A

[0646] Ketone A (from step 1 above) was synthesized from galactose according to the following literature:

[0647] A Cavezza, C.Boulle, A.Guéguiniat, P.Pichaud, S.Trouiie, L.Ricard, M.Dalko-Csiba, Bioorgnic&Medicinal Chemistry Letters 2009, 19, 845-849

[0648] Preparation of ketone B

[0649] Acetic anhydride (4.72 mL, 4.72 mmol) was added dropwise to a stirred suspension of known ketone A (1.81 g, 8.1 mmol) in dichloromethane (8 mL) and pyridine (4.90 mL, 60.0 mmol) at 0 °C. The resulting reaction mixture was warmed to room temperature and stirred overnight (approximately 16 hours). The reaction mixture was poured into water and extracted with dichloromethane (3 × 50 mL). All combined organic phases were washed with 3 M HCl (3 × 50 mL), saturated NaHCO3 (50 mL), and brine (50 mL). The mixture was dried over MgSO4 and evaporated to obtain a resinous substance, which was purified by silica gel chromatography (1:1 to 0:1 gasoline: Et2O) to give tetraacetate ketone B (2.87 g, 7.43 mmol, 57%) as a pale yellow solid.

[0650] Preparation of alcohol C

[0651] MeMgBr (1.4 M, 1.85 mL, 2.6 mmol) was added dropwise to a stirred solution of ketone B (420 mg, 1.08 mmol) in THF (10 mL) at -78 °C. The resulting solution was stirred at -78 °C for 4 hours. The reaction was quenched by adding saturated ammonium chloride aqueous solution (20 mL) and extracted with EtOAc (3 × 25 mL). All combined organic phases were washed with brine (25 mL), dried over MgSO4 and evaporated to give a resinous substance, which was subjected to silica gel chromatography (1:1 to 0:1 gasoline:EtOAc) to give a colorless solid of alcohol C (133 mg, 0.328 mmol, 30.5%).

[0652] Preparation of ester D

[0653] DCC coupling was performed according to a slightly modified method and procedure reported in Tetrahedron Lett. 2012, 53, 879. Linolenic acid (94.5 mg, 0.34 mmol), dicyclohexylcarbodiimide (70.6 mg, 0.34 mmol), and DMAP (8.4 mg, 0.068 mmol) were added to a stirred solution of alcohol C (126 mg, 0.31 mmol) in dichloromethane (6 mL) at room temperature and under an argon atmosphere. The reaction mixture was stirred overnight at room temperature (approximately 16 hours). The reaction was cooled to -20 °C and filtered. All filtrates were evaporated under reduced pressure, and the mixture was purified by silica gel chromatography (8:1 to 4:1 gasoline:EtOAc) to obtain a colorless, oily ester D (115 mg, 0.173 g mmol, 55.8%).

[0654] Preparation of compound 139

[0655] Deprotection was performed according to the methods and procedures reported in Tetrahedron Lett. 2012, 53, 879.

[0656] Hydrazine monohydrate (63 μL, 1.26 mmol) was added to a stirred solution of ester D (105 mg, 0.158 mmol) in 85% aqueous ethanol (5 mL) at 44 °C. The reaction mixture was stirred at 44 °C for 4 hours. The solvent was removed under a nitrogen stream, and the residue was purified by silica gel chromatography (10:1 dichloromethane:MeOH) to give a colorless oily compound 139 (38 mg, 0.077 mmol, 48%).

[0657] Synthetic routes for compounds 99, 218, 184, 215 and 46

[0658] The modified linker units used in compounds 99, 218, 184, 215, and 46 (where an additional CH2 is present in the linker unit) are not commercially available compared to the linker units shown in the reaction diagrams in the Tetrahedron Letters above; however, these are known compounds whose synthesis has been reported in the following literature:

[0659] C.Iwata, N.Maezaki, K.Hattori, M.Fujita, Y.Moritani, Y.Takemoto, T.Tanaka, T.Imanishi, Chemical, and Pharmaceutical Bulletin, 1993, 41, (2), 339-345

[0660] R.Schillera, L.Tichotovaa, J.Pavlika, V.Buchtab, B Melicharc, I.Votrubad, J.unesa, M.Spulaka, M.Poura, Bioorganic&Medicinal Chemistry Letters, 2010, 20, (24), 7358-7360

[0661] HABates, J. Farina, M. Tong, J. Org. Chem., 1986, 51(14), 2637-2641.

[0662] The connecting base units are therefore synthesized according to known methods prior to the reaction diagram scheme used for Tetrahedron Letters.

[0663] To illustrate this point, the synthetic route for compound 46 is as follows:

[0664]

[0665] This synthesis exemplifies the direct nature of the changes required to synthesize compounds with altered linker units using the reaction diagrammatic scheme described in the aforementioned Tetrahedron Letters paper by Manzo, E. et al.

[0666] It should be noted that this pathway is almost identical to that described in the Tetrahedron Letters paper, but differs in step 4, where the modified alcohol is used to modify the linker unit. The preparation of this modified alcohol can be found in J. Org. Chem. 1986, 51, 2637 (it is structure 14 in that paper).

[0667] It is easy to see the modification of the above synthetic route for compound 46, which would be needed to achieve compounds 99, 218, 184, and 215 (which also include modified linker units). The differences lie in the choice of sugar, whether or not it is protected, and the choice of R and R' groups.

[0668] Synthetic routes of compounds 146 and 154

[0669]

[0670] Preparation of compound 146

[0671] Linolenic acid (278 mg, 1.0 mmol), dicyclohexylcarbodiimide (206 mg, 1.0 mmol), and DMAP (24 mg, 0.2 mmol) were added to a commercially available galactose diacetone compound (260 mg, 1.00 mmol) in a stirred solution of dichloromethane (10 mL) at room temperature under an argon atmosphere. The reaction mixture was stirred overnight at room temperature (approximately 16 hours). The reaction was cooled to -20 °C and filtered. The filtrate was evaporated under reduced pressure, and the mixture was purified by silica gel chromatography (8:1 to 2:1 gasoline:Et2O) to give a colorless oily compound 146 (438 mg, 0.84 mmol, 84%).

[0672] Preparation of compound 154

[0673] Trifluoroacetic acid (1 mL) was added to a stirred solution of compound 146 (106 mg, 0.20 mmol) in DCM (1 mL) at 0 °C, and the reaction was stirred for 12 h. The reactants were evaporated under reduced pressure, and the residue was purified by silica gel chromatography (10:1 DCM:MeOH) to give compound 154 (60 mg, 0.136 mmol, 68%) as a mixture of terminal isomers in a colorless oil.

Claims

1. A compound having the following formula: ###0001### or a pharmaceutically acceptable salt thereof. 。 2. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.

3. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent.

4. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable excipient.

5. The pharmaceutical composition of any one of claims 2-4, wherein the composition further comprises at least one additional anti-cancer agent.

6. A kit comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and an anti-cancer agent, wherein the anti-cancer agent is provided with instructions for administration in a daily dose that is 10% or more less than the dose when the anti-cancer agent is administered alone.

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