CN115916195A - Therapeutic agents and uses thereof - Google Patents
Therapeutic agents and uses thereof Download PDFInfo
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- CN115916195A CN115916195A CN202080102648.3A CN202080102648A CN115916195A CN 115916195 A CN115916195 A CN 115916195A CN 202080102648 A CN202080102648 A CN 202080102648A CN 115916195 A CN115916195 A CN 115916195A
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
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Abstract
Therapeutic compositions for humans are provided, including compounds comprising a plurality of fused polycyclic moieties and a linker moiety. In certain embodiments, the compound is the reaction product of an aldehyde and a hamalin component. The compositions exhibit anti-cancer properties, particularly against lymphoma, leukemia, pancreas, endometrium, ovary, stomach, breast, kidney, cervix, head and neck, and myeloma cell lines.
Description
Background
Technical Field
The present invention relates to chemotherapeutic agents for use in the treatment of humans, and in particular for use in the treatment of human cancer, and corresponding methods for the treatment of humans suffering from cancer or other diseases. The invention further provides dosage forms and regimens for administration to human patients, and methods of formulating and administering such dosage forms to produce improved therapeutic results. More particularly, the invention relates to the administration of particular chemotherapeutic dosage forms (e.g., liquid mixtures, capsules, pills, or tablets) comprising a compound or agent having a plurality of fused polycyclic moieties linked or tethered by suitable linkers. In certain embodiments, compounds having multiple β -carboline component moieties and a single linker moiety are provided.
Description of the Related Art
Cancer is a general term for a large group of diseases that can affect any part of the body. Other terms used are malignant tumors and neoplasms. One decisive feature of cancer is the rapid generation of abnormal cells that grow beyond their usual boundaries and can then invade the adjacent parts of the body and spread to other organs. This process is called migration. Metastasis is the leading cause of death from cancer.
Transformation of normal cells into tumor cells is a multi-stage process, usually from precancerous disease to malignant tumor progression. These changes are the result of interactions between human genetic factors and three classes of external factors, including:
physical carcinogens, such as ultraviolet light and ionizing radiation
Chemical carcinogens, such as asbestos, components of tobacco smoke, aflatoxins (a food pollutant) and arsenic (a drinking water pollutant)
Biological carcinogens, such as infections with certain viruses, bacteria or parasites.
Some examples of infections associated with certain cancers:
viruses: hepatitis b and liver cancer, human Papilloma Virus (HPV) and cervical cancer, as well as Human Immunodeficiency Virus (HIV) and kaposi's sarcoma.
The bacteria: helicobacter pylori and gastric cancer.
Parasites: schistosomiasis and bladder cancer.
Aging is another fundamental factor in the development of cancer. The incidence of cancer rises dramatically with age, most likely due to the accumulation of risk for a particular cancer with age. As people age, the overall risk accumulation is combined with a trend toward less effective cell repair mechanisms.
In low and medium income countries, smoking, drinking, low intake of fruits and vegetables, and chronic infection with Hepatitis B (HBV), hepatitis C Virus (HCV) and some types of Human Papilloma Virus (HPV) are major risk factors for cancer. Cervical cancer caused by HPV is a major cause of cancer death in women in low-income countries. In high-income countries, smoking, drinking, and being overweight or obese are major risk factors for cancer.
The most common forms of cancer treatment are surgery, chemotherapy, and radiation therapy. All of these techniques have significant drawbacks in terms of side effects and patient discomfort. For example, chemotherapy may result in a significant decrease in white blood cell count (neutropenia), red blood cell count (anemia), and platelet count (thrombocytopenia). This can lead to pain, diarrhea, constipation, mouth sores, hair loss, nausea and vomiting.
Biological therapy (sometimes referred to as immunotherapy, biotherapy or biological response modifier therapy) is a relatively new complement of the cancer treatment family. Biological therapies utilize the body's immune system, directly or indirectly, to combat cancer or mitigate the side effects that some cancer treatments may cause.
Adverse drug events are common during chemotherapy involving multiple drug treatments, and indeed, toxicity associated with drug-drug interactions is one of the leading causes of hospitalization in the united states. "Drug-Drug Interactions: an immunogenic Attribute in Drugs" Drugs Today 39.5 (2003): 308-338. Indeed, adverse drug reactions were reported in one fifth of all investigated adults in the united states during any one month period. Hakkarainen, K.M.et. "Presence and received preventility of Self-Reported additive Drug Events-A promotion-Based measures of 7,099 additives." PLoS One 8.9 (2013): e73166. A large-scale study of adults 57-85 years of age found that over five prescription drugs were taken in 29% of the population, and nearly 5% of the population were exposed to a serious risk of adverse drug-drug interactions. In the field of oncology, a review of over 400 cancer patients determined that 77% of patients were considered to have a moderately severe potential for adverse drug interactions and 9% of patients had severe adverse drug interactions. Ghalib, M.S. et al, "alternatives of Chemotherapeutic pharmacocokinetic Profiles by Drug-Drug interactions," Expert Opin Drug Metabl. Toxicol 5.2 (2009): 109-130.
Such interactions are a global health problem, and the WHO has determined that adverse drug interactions are a major cause of morbidity and mortality worldwide, with up to 7% of all hospitalizations being due to adverse drug interactions in the united states. A recent survey in one hospital has shown that 83% of hospitalized patients are taking a prescribed combination of drugs that may cause adverse reactions. Patel, P.S.et. "A Study of positional Adverse Drug-Drug Interactions Among described Drugs in a medical external Department of a diagnostic Care testing Hospital." J.basic Clin.Pharm.5.2 (2014): 44-48.
Examples of well-known adverse drug interactions include the development of rhabdomyolysis (a serious muscle disorder) when simvastatin and amiodarone are taken. Thus, the FDA has introduced warnings on interactions on drug labels. The calcium channel blocker Mibefradif taken due to hypertension was removed from the market due to deleterious interactions with drugs that affect the electrical activity of the heart.
U.S. patent No. 8,039.025, which is incorporated herein by reference in its entirety, describes cancer treatment in the form of an extract of arisaema basitamanum (Arum palaestin Boiss) supplemented with individual amounts of beta-sitosterol, isovanillin, and linoleic acid.
U.S. patent No. 9,402,834, published 2016, 8, 2, describes anticancer compositions comprising various components in a mixture, such as a mixture of curcumin, harmine and isovanillin components, or a mixture of components comprising curcumin/harmine, curcumin/isovanillin and harmine/isovanillin components.
Despite the extensive research and effort worldwide to counter the trend towards cancer and its side effects, many of the clinical manifestations of the disease remain a huge problem. Thus, any new cancer treatment with the ability of the therapeutic effect to affect and/or ameliorate the symptoms of the cancer and improve the patient's lifestyle is highly significant and important.
Disclosure of Invention
The present invention provides compositions useful as improved chemotherapeutic agents for the treatment of humans, and in particular for the treatment of human cancer, as well as corresponding methods for preparing such compositions and uses thereof. In general, the chemotherapeutic agents of the invention include (or consist essentially of, or consist of) one or more compounds and related forms thereof. Thus, as used herein in the specification and claims, the definition of "therapeutic compound" or "compound" means the defined compound itself, as well as dimers, isomers, tautomers, derivatives, solvates, metabolites, esters, metal complexes (e.g., cu, fe, zn, pt, V), prodrugs and salts thereof. Thus, "dimer" refers to a molecule or molecular complex consisting of two identical molecules that are linked together by a bond that may be strong or weak (e.g., a covalent or hydrogen bond); "isomers" refers to each of two or more compounds having the same molecular formula but different arrangements of atoms, and includes structural isomers and stereoisomers (e.g., geometric isomers and enantiomers); "tautomer" refers to two or more equiaxed compounds in equilibrium, such as keto-enol and imine and enamine tautomers; "derivative" means a compound that can be imagined as being produced from a defined parent compound by substituting one atom with another atom or group of atoms or as actually synthesized therefrom; "solvate" refers to a substance that interacts with a defined compound and a solvent to form a stable solute; "metabolite" refers to a defined compound that is metabolized in vivo by digestion or other bodily chemical processes; and "prodrug" refers to a defined compound that results from a metabolic process. The compounds may be used directly in partially or substantially completely purified form, or may be modified as indicated above. The compounds may be in crystalline or amorphous form, and may be lyophilized.
The invention also provides novel methods for treating cancer by administering appropriate amounts of compositions comprising therapeutic compounds as described herein. These compositions are therefore particularly designed for use in the treatment of cancer, and these compositions can be used in the manufacture of medicaments for anticancer therapeutic applications. Furthermore, the present invention provides a composition for treating cancer comprising administering a therapeutically effective amount of the novel composition with a pharmaceutically acceptable carrier prepared by a process known per se.
As used herein, "chemotherapeutic agent" or simply "therapeutic agent" refers to one or more compounds described herein that are useful for treating human conditions, particularly human cancer. Chemotherapeutic agents can be cytostatic, selectively toxic, or destructive to cancer tissues and/or cells, including cancer stem cells, but also include indiscriminate cytotoxic compounds for cancer therapy.
The therapeutic compounds or agents of the invention have been found to be effective in the treatment of a variety of human cancer cells, and in particular lymphoma, leukemia, pancreatic cancer, endometrial cancer, ovarian cancer, gastric cancer, breast cancer, renal cancer, cervical cancer, head and neck cancer, and myeloma.
The compounds or agents of the present invention broadly include a plurality of fused polycyclic moieties linked or tethered by suitable linkers; preferably there are two tricyclic moieties. The polycyclic moieties each include at least one N-containing ring. Beta-carboline moieties are particularly useful in the present invention, such as hamaline (harmaline) or similar moieties. In certain embodiments, a pair of β -carboline moieties are bonded through a linker moiety, and in particular through a single atom forming at least a portion of the entire linker. The reaction product of the beta-carboline compound and the aldehyde compound produces a number of useful anti-cancer compounds according to the present invention. While the compounds of the present invention, per se, are not part of an anti-cancer composition and do not include compounds consisting of the reaction product of two hamaline moieties or two harmine moieties with a linker moiety of benzaldehyde of p-nitrobenzaldehyde, the anti-cancer compositions (which typically include at least one other agent, component or compound) and methods of treatment of the present invention do include such compounds.
Drawings
Figure 1 is a graph of the number of cells versus dose number of o-vanillin/hamalin compound (GZ 523.001) demonstrating its role in inducing lymphoma cell death as described in example 2:
figure 2 is a graph of the number of cells versus dose number of o-vanillin/hamalin compound (GZ 523.002) demonstrating its role in inducing lymphoma cell death as described in example 2:
figure 3 is a graph of cell number versus dose number for o-vanillin/hamalin compound (GZ 523.003), demonstrating its role in inducing lymphoma cell death, as described in example 2:
figure 4 is a graph of cell number versus dose number for o-vanillin/hamalin compound (GZ 523.004) demonstrating its effect in inducing lymphoma cell death as described in example 2:
figure 5 is a graph of the number of cells versus dose number for o-vanillin/hamalin compound (GZ 523.005) demonstrating its role in inducing lymphoma cell death as described in example 2:
figure 6 is a graph of the number of cells versus dose number for o-vanillin/hamalin compound (GZ 523.006) demonstrating its effect in inducing lymphoma cell death as described in example 2:
figure 7 is a graph of cell number versus dose number for o-vanillin/hamalin compound (GZ 523.007), demonstrating its effect in inducing lymphoma cell death, as described in example 2:
figure 8 is a graph of cell number versus dose number for o-vanillin/hamalin compound (GZ 523.008) demonstrating its role in inducing lymphoma cell death as described in example 2:
figure 9 is a graph of the number of cells versus dose number for o-vanillin/hamalin compound (GZ 523.001) demonstrating its effect in inducing leukemia cell death, as described in example 2:
figure 10 is a graph of cell number versus dose number for o-vanillin/hamalin compound (GZ 523.002) demonstrating its effect in inducing leukemia cell death as described in example 2:
figure 11 is a graph of the number of cells versus dose number for o-vanillin/hamalin compound (GZ 523.003), demonstrating its effect in inducing leukemia cell death, as described in example 2:
figure 12 is a graph of cell number versus dose number for o-vanillin/hamalin compound (GZ 523.004) demonstrating its effect in inducing leukemia cell death as described in example 2:
figure 13 is a graph of the number of cells versus dose number for o-vanillin/hamalin compound (GZ 523.005) demonstrating its effect in inducing leukemia cell death, as described in example 2:
figure 14 is a graph of cell number versus dose number for o-vanillin/hamalin compound (GZ 523.006) demonstrating its effect in inducing leukemia cell death as described in example 2:
figure 15 is a graph of cell number versus dose number for o-vanillin/hamalin compound (GZ 523.007), demonstrating its effect in inducing leukemia cell death, as described in example 2:
figure 16 is a graph of the number of cells versus dose number for o-vanillin/hamalin compound (GZ 523.008) demonstrating its effect in inducing leukemia cell death as described in example 2:
figure 17 is a graph of cell number versus dose number for compositions comprising one or more high molecular weight di-oligomer compounds derived from o-vanillin/hamalin response, demonstrating its role in inducing lymphoma cell death, as described in example 3;
figure 18 is a graph of cell number versus dose number for compositions comprising one or more high molecular weight di-oligomeric compounds derived from o-vanillin/hamalin reaction, demonstrating their effect in inducing leukemia cell death, as described in example 3;
figure 19 is a graph of cell number versus dose number for vanillin/hamstring compound (GZ 518.000) demonstrating its role in inducing lymphoma cell death as described in example 5;
figure 20 is a graph of cell number versus dose number for vanillin/hamalin compound (GZ 518.001), demonstrating its role in inducing lymphoma cell death, as described in example 5;
FIG. 21 is a graph showing confirmation by treatment of multiple lymphoma cell lines with GZ523.006Fixed EC 50 Bar graph of values, as explained in example 6;
fig. 22 is a bar graph depicting the results of a caspase 3/7 assay using GZ523.006 as compared to multiple lymphoma cell lines, demonstrating the cytotoxic properties of GZ523.006 by induction of apoptosis;
FIG. 23 is a graph showing cell growth as a function of concentration of 518B562 compound in the MIA PaCa-2 cell proliferation assay described in example 8;
FIG. 24 is a graph showing cell growth as a function of concentration of 518B562 compound in the ASPC-1 cell proliferation assay described in example 8;
FIG. 25 is a graph showing cell growth as a function of concentration of 518B562 compound in the BxPC-3 cell proliferation assay described in example 8;
figure 26 is a graph showing cell growth as a function of concentration of 518B562 compound in the AN3CA cell proliferation assay described in example 8;
FIG. 27 is a graph showing cell growth as a function of concentration of 518B562 compound in the HEC-1a cell proliferation assay described in example 8;
FIG. 28 is a graph showing cell growth as a function of concentration of 518B562 compound in the MDA-MB-231 cell proliferation assay described in example 8;
FIG. 29 is a graph showing cell growth as a function of concentration of 518B562 compound in the MDA-MB-468 cell proliferation assay described in example 8;
figure 30 is a graph showing cell growth as a function of concentration of 518B562 compound in the HCC70 cell proliferation assay described in example 8;
figure 31 is a graph showing cell growth as a function of concentration of 518B562 compound in the H1975 cell proliferation assay described in example 8;
FIG. 32 is a graph showing cell growth as a function of concentration of 518B562 compound in the H1650 cell proliferation assay described in example 8;
figure 33 is a graph showing cell growth as a function of concentration of 518B562 compound in the a2780 cell proliferation assay described in example 8;
figure 34 is a graph showing cell growth as a function of concentration of 518B562 compound in the a2780CP cell proliferation assay described in example 8;
figure 35 is a graph showing cell growth as a function of concentration of the 518B562 compound in the RXF-393 cell proliferation assay described in example 8;
figure 36 is a graph showing cell growth as a function of concentration of 518B562 compound in a498 cell proliferation assay described in example 8;
figure 37 is a graph showing cell growth as a function of concentration of 518B562 compound in the N87 cell proliferation assay described in example 8;
figure 38 is a graph showing cell growth as a function of concentration of 518B562 compound in the SiHA cell proliferation assay described in example 8;
figure 39 is a graph showing cell growth as a function of concentration of 518B562 compound in the FaDu cell proliferation assay described in example 8;
FIG. 40 is a graph showing cell growth as a function of concentration of the 518B562 compound in a DOHH-2 cell proliferation assay described in example 8;
FIG. 41 is a graph showing cell growth as a function of concentration of 518B562 compound in the SU-DHL-4 cell proliferation assay described in example 8;
FIG. 42 is a graph showing cell growth as a function of concentration of 518B562 compound in the OCI-LY3 cell proliferation assay described in example 8;
fig. 43 is a graph showing cell growth as a function of concentration of the 518B562 compound in the JIM1 cell proliferation assay described in example 8;
FIG. 44 is a graph showing cell growth as a function of concentration of 518B562 compound in the KMM-1 cell proliferation assay described in example 8;
FIG. 45 is a graph showing cell growth as a function of concentration of 518B562 compound in the KMS-11 cell proliferation assay described in example 8;
FIG. 46 is a graph showing cell growth as a function of concentration of 518B562 compound in the KMS-27 cell proliferation assay described in example 8;
FIG. 47 is a graph showing cell growth as a function of concentration of 518B562 compound in the KMS-34 cell proliferation assay described in example 8;
figure 48 is a graph showing cell growth as a function of concentration of 518B562 compound in the H929 cell proliferation assay described in example 8;
figure 49 is a graph showing cell growth as a function of concentration of 518B562 compound in the L363 cell proliferation assay described in example 8;
figure 50 is a graph showing cell growth as a function of concentration of 518B562 compound in the mm.1s cell proliferation assay described in example 8;
FIG. 51 is a graph showing cell growth as a function of concentration of 518B562 compound in the MOLP-8 cell proliferation assay described in example 8;
FIG. 52 is a graph showing cell growth as a function of concentration of the 518B562 compound in the Jeko-1 parental cell proliferation assay described in example 8;
FIG. 53 is a graph showing cell growth as a function of concentration of 518B562 compound in a Jeko-1 lenalidomide (Lenalidomide) resistant cell proliferation assay described in example 8;
FIG. 54 is a graph showing cell growth as a function of concentration of 518B562 compound in a Jeko-1 Bortezomib (Bortezomib) resistant cell proliferation assay described in example 8;
FIG. 55 is a graph showing cell growth as a function of concentration of 560 compound in the MIA PaCa-2 cell proliferation assay described in example 8;
FIG. 56 is a graph showing cell growth as a function of concentration of 560 compound in the ASPC-1 cell proliferation assay described in example 8;
FIG. 57 is a graph showing cell growth as a function of concentration of 560 compound in the BxPC-3 cell proliferation assay described in example 8;
figure 58 is a graph showing cell growth as a function of concentration of 560 compound in the AN3CA cell proliferation assay described in example 8;
FIG. 59 is a graph showing cell growth as a function of concentration of 560 compound in the HEC-1a cell proliferation assay described in example 8;
FIG. 60 is a graph showing cell growth as a function of concentration of 560 compound in the MDA-MB-231 cell proliferation assay described in example 8;
FIG. 61 is a graph showing cell growth as a function of concentration of 560 compound in the MDA-MB-468 cell proliferation assay described in example 8;
figure 62 is a graph showing cell growth as a function of concentration of 560 compounds in the HCC70 cell proliferation assay described in example 8;
FIG. 63 is a graph showing cell growth as a function of concentration of 560 compounds in the H1975 cell proliferation assay described in example 8;
FIG. 64 is a graph showing cell growth as a function of concentration of 560 compound in the H1650 cell proliferation assay described in example 8;
figure 65 is a graph showing cell growth as a function of concentration of 560 compound in the a2780 cell proliferation assay described in example 8;
FIG. 66 is a graph showing cell growth as a function of concentration of 560 compound in the A2780CP cell proliferation assay described in example 8;
figure 67 is a graph showing cell growth as a function of concentration of 560 compound in the RXF-393 cell proliferation assay described in example 8;
figure 68 is a graph showing cell growth as a function of concentration of 560 compound in a498 cell proliferation assay described in example 8;
figure 69 is a graph showing cell growth as a function of concentration of 560 compound in the N87 cell proliferation assay described in example 8;
figure 70 is a graph showing cell growth as a function of concentration of 560 compound in the SiHA cell proliferation assay described in example 8;
figure 71 is a graph showing cell growth as a function of concentration of 560 compound in the FaDu cell proliferation assay described in example 8;
figure 72 is a graph showing cell growth as a function of concentration of 560 compound in the DOHH-2 cell proliferation assay described in example 8;
FIG. 73 is a graph showing cell growth as a function of concentration of 560 compound in the SU-DHL-4 cell proliferation assay described in example 8;
FIG. 74 is a graph showing cell growth as a function of concentration of 560 compound in an OCI-LY3 cell proliferation assay described in example 8;
fig. 75 is a graph showing cell growth as a function of the concentration of 560 compound in the JIM1 cell proliferation assay described in example 8;
FIG. 76 is a graph showing cell growth as a function of concentration of 560 compound in the KMM-1 cell proliferation assay described in example 8;
FIG. 77 is a graph showing cell growth as a function of concentration of 560 compound in the KMS-11 cell proliferation assay described in example 8;
FIG. 78 is a graph showing cell growth as a function of concentration of 560 compound in the KMS-27 cell proliferation assay described in example 8;
FIG. 79 is a graph showing cell growth as a function of concentration of 560 compound in the KMS-34 cell proliferation assay described in example 8;
figure 80 is a graph showing cell growth as a function of concentration of 560 compound in the H929 cell proliferation assay described in example 8;
figure 81 is a graph showing cell growth as a function of concentration of 560 compound in the L363 cell proliferation assay described in example 8;
figure 82 is a graph showing cell growth as a function of concentration of 560 compound in the mm.1s cell proliferation assay described in example 8;
FIG. 83 is a graph showing cell growth as a function of concentration of 560 compound in the MOLP-8 cell proliferation assay described in example 8;
FIG. 84 is a graph showing cell growth as a function of concentration of 560 compound in the Jeko-1 parental cell proliferation assay described in example 8;
FIG. 85 is a graph showing cell growth as a function of concentration of 560 compound in a Jeko-1 lenalidomide resistant cell proliferation assay described in example 8;
FIG. 86 is a graph showing cell growth as a function of concentration of 560 compound in the Jeko-1 bortezomib-resistant cell proliferation assay described in example 8;
FIG. 87 is a graph showing cell growth as a function of concentration of 561 compound in the MIA PaCa-2 cell proliferation assay described in example 8;
FIG. 88 is a graph showing cell growth as a function of concentration of 561 compound in the ASPC-1 cell proliferation assay described in example 8;
FIG. 89 is a graph showing cell growth as a function of concentration of 561 compound in the BxPC-3 cell proliferation assay described in example 8;
figure 90 is a graph showing cell growth as a function of concentration of compound 561 in the AN3CA cell proliferation assay described in example 8;
FIG. 91 is a graph showing cell growth as a function of concentration of 561 compound in the HEC-1a cell proliferation assay described in example 8;
FIG. 92 is a graph showing cell growth as a function of concentration of 561 compound in the MDA-MB-231 cell proliferation assay described in example 8;
FIG. 93 is a graph showing cell growth as a function of concentration of 561 compound in the MDA-MB-468 cell proliferation assay described in example 8;
figure 94 is a graph showing cell growth as a function of concentration of compound 561 in the HCC70 cell proliferation assay described in example 8;
figure 95 is a graph showing cell growth as a function of concentration of 561 compound in the H1975 cell proliferation assay described in example 8;
figure 96 is a graph showing cell growth as a function of concentration of compound 561 in the H1650 cell proliferation assay described in example 8;
figure 97 is a graph showing cell growth as a function of concentration of 561 compound in the a2780 cell proliferation assay described in example 8;
FIG. 98 is a graph showing cell growth as a function of concentration of 561 compound in the A2780CP cell proliferation assay described in example 8;
figure 99 is a graph showing cell growth as a function of concentration of 561 compound in the RXF-393 cell proliferation assay described in example 8;
figure 100 is a graph showing cell growth as a function of concentration of 561 compound in a498 cell proliferation assay described in example 8;
figure 101 is a graph showing cell growth as a function of concentration of 561 compound in the N87 cell proliferation assay described in example 8;
figure 102 is a graph showing cell growth as a function of concentration of 561 compound in the SiHA cell proliferation assay described in example 8;
figure 103 is a graph showing cell growth as a function of concentration of 561 compound in the FaDu cell proliferation assay described in example 8;
FIG. 104 is a graph showing cell growth as a function of concentration of 561 compound in a DOHH-2 cell proliferation assay described in example 8;
FIG. 105 is a graph showing cell growth as a function of concentration of 561 compound in the SU-DHL-4 cell proliferation assay described in example 8;
FIG. 106 is a graph showing cell growth as a function of concentration of compound 561 in the OCI-LY3 cell proliferation assay described in example 8;
fig. 107 is a graph showing cell growth as a function of the concentration of the compound 561 in the JIM1 cell proliferation assay described in example 8;
FIG. 108 is a graph showing cell growth as a function of concentration of 561 compound in the KMM-1 cell proliferation assay described in example 8;
FIG. 109 is a graph showing cell growth as a function of concentration of 561 compound in the KMS-11 cell proliferation assay described in example 8;
FIG. 110 is a graph showing cell growth as a function of concentration of 561 compound in the KMS-27 cell proliferation assay described in example 8;
FIG. 111 is a graph showing cell growth as a function of concentration of 561 compound in the KMS-34 cell proliferation assay described in example 8;
figure 112 is a graph showing cell growth as a function of concentration of 561 compound in the H929 cell proliferation assay described in example 8;
figure 113 is a graph showing cell growth as a function of concentration of compound 561 in the L363 cell proliferation assay described in example 8;
figure 114 is a graph showing cell growth as a function of concentration of 561 compound in the mm.1s cell proliferation assay described in example 8;
FIG. 115 is a graph showing cell growth as a function of concentration of 561 compound in the MOLP-8 cell proliferation assay described in example 8;
FIG. 116 is a graph showing cell growth as a function of concentration of the 561 compound in the Jeko-1 parent cell proliferation assay described in example 8;
FIG. 117 is a graph showing cell growth as a function of concentration of 561 compound in the Jeko-1 lenalidomide resistant cell proliferation assay described in example 8;
FIG. 118 is a graph showing cell growth as a function of concentration of 561 compound in the Jeko-1 bortezomib-resistant cell proliferation assay described in example 8;
FIG. 119 is a graph showing cell growth as a function of determined concentration of 560 compound in the S2-007 pancreatic ductal adenocarcinoma cell proliferation assay described in example 15;
figure 120 is a graph showing cell growth as a function of determined concentration of 560 compound in the MiaPaCa-2 pancreatic ductal adenocarcinoma cell proliferation assay described in example 15;
FIG. 121 is a graph showing cell growth as a function of determined concentration of 562 compound in the S2-007 pancreatic ductal adenocarcinoma cell proliferation assay described in example 15;
figure 122 is a graph showing cell growth as a function of determined concentration of 562 compound in the MiaPaCa-2 pancreatic ductal adenocarcinoma cell proliferation assay described in example 15;
FIG. 123 is a series of photographs depicting colony formation as a function of determined concentration of 560 compound in the S2-007 pancreatic ductal adenocarcinoma cell colony formation assay described in example 16;
figure 124 is a series of photographs depicting colony formation as a function of determined concentration of 560 compound in the MiaPaCa-2 pancreatic ductal adenocarcinoma cell colony formation assay described in example 16;
FIG. 125 is a series of photographs depicting colony formation as a function of concentration of determined 562 compounds in the S2-007 pancreatic ductal adenocarcinoma cell colony formation assay described in example 16;
figure 126 is a series of photographs depicting colony formation as a function of determined concentration of 562 compound in the MiaPaCa-2 pancreatic ductal adenocarcinoma cell colony formation assay described in example 16;
figure 127 is an additional series of photographs depicting colony formation as a function of the concentration of compound determined 562 in the MiaPaCa-2 pancreatic ductal adenocarcinoma cell colony formation assay described in example 16;
FIG. 128 is a set of bar graphs showing the results of cell cycle assays performed using the identified 560 compound with S2-007 cells over 24 hours and 48 hours, as described in example 17, with Sub G0;
FIG. 128A is a set of bar graphs showing the results of cell cycle assays performed using the identified 560 compound with S2-007 cells over 24 hours and 48 hours, as described in example 17, without Sub G0;
figure 129 is a set of bar graphs showing the results of cell cycle assays performed using the identified 560 compound with MiaPaCa-2 cells over 24, 48, and 72 hours, as described in example 17, with Sub G0;
figure 129A is a set of bar graphs showing the results of cell cycle assays performed with MiaPaCa-2 cells over 24, 48, and 72 hours using the identified 560 compound, without Sub G0, as described in example 17;
FIG. 130 is a set of bar graphs showing the results of cell cycle assays using established 562 compounds with S2-007 cells over 24, 48, and 72 hours, as described in example 17, with Sub G0;
FIG. 130A is a set of bar graphs showing the results of cell cycle assays performed using the identified 562 compound with S2-007 cells over 24, 48, and 72 hours, as described in example 17, without Sub G0;
figure 131 is a set of bar graphs showing the results of cell cycle assays using identified 562 compounds with MiaPaCa-2 cells over 24, 48, and 72 hours, as described in example 17, with Sub G0; and
figure 131A is a set of bar graphs showing the results of cell cycle assays performed using identified 562 compounds with MiaPaCa-2 cells over 24, 48, and 72 hours, as described in example 17, without Sub G0.
Detailed Description
The therapeutic agents of the present invention are used in therapeutically effective amounts, i.e., amounts that will elicit the biological or medical response of the tissue, system or subject sought, and in particular, elicit some desired therapeutic effect against a variety of human diseases, and in particular, cancer; in the case of cancer, these agents operate by preventing and/or inhibiting the proliferation and/or survival of cancer cells (including cancer stem cells) and/or by slowing the progression of the cancer. One skilled in the art recognizes that even if the condition is not completely eradicated or prevented, but it or its symptoms and/or effects are partially ameliorated or alleviated in the subject, then that amount may be considered therapeutically effective. The appropriate composition of the agents herein and the dosage regimen for use of such agents will, of course, depend on the particular cancer being treated, the extent of the disease, and other factors relevant to the patient as determined by one of skill in the art. Thus, the term "treated" or "treatment" as used herein refers to a product or process according to the present invention that is intended to produce a beneficial alteration in an existing condition (e.g., cancerous tissue, tumor size, metastasis, etc.) in a subject, such as by reducing the severity of clinical symptoms and/or the effect of the condition, and/or reducing the duration of symptoms/effects in the subject.
The chemotherapeutic agents of the invention may include additional ingredients for administration to a subject. Such additional ingredients include other active agents, preservatives, buffers, salts, carriers, excipients, diluents or other pharmaceutically acceptable ingredients. Active agents that may be included in the compositions include antiviral, antibiotic or other anti-cancer compounds; the latter may include compounds described in PCT application serial No. PCT/US2015/055968, such as curcumin, harmine, and isovanillin, as well as metabolites, dimers, derivatives, isomers, enantiomers (both D and L), tautomers, esters, complexes, and salts of any of the foregoing.
The therapeutic agents of the present invention give significant and unexpected therapeutic results, particularly in the context of anti-cancer results. In use, a therapeutically effective amount of an agent or composition according to the invention is administered to a subject in need thereof. This may include a single unit dose, or more typically, a lower dose is administered over a period of time (e.g., daily).
The dosage may be administered in any convenient manner, such as orally, rectally, nasally, ocularly, parenterally (including intraperitoneally, gastrointestinal tract, intrathecally, intravenously, dermally (e.g., dermal patches), subcutaneously (e.g., by injection or implantation), or intramuscularly. The dosage forms of the present invention may be in the form of a liquid, gel, suspension, solution, or solid (e.g., tablets, pills, or capsules). In addition, a therapeutically effective amount of an agent of the invention may be co-administered with one or more other chemotherapeutic agents, wherein the two products are administered substantially simultaneously or in any sequential manner.
Dosage levels for use of the compositions of the present invention are highly variable due to factors such as the age of the patient, the physical condition of the patient, the weight, the type of condition or conditions being treated (e.g., the particular cancer or cancers), and the severity of the condition. In general, however, regardless of the dosage form or route of administration, such as liquid solutions or suspensions, capsules, pills, or tablets, the compositions should be administered by oral, parenteral, or injection at about 5 to 2000mg per day, and more typically at about 100-800mg per day. Such dosages may be based on once daily administration, but are more typically administered multiple times per day.
Additional advantages of various embodiments of the present invention will be apparent to those skilled in the art upon review of the disclosure herein and the working examples below. It should be understood that the various embodiments described herein are not necessarily mutually exclusive, unless stated otherwise herein. For example, features described or depicted in one embodiment may also be included in other embodiments, but are not necessarily included. Thus, the present invention encompasses various combinations and/or subcombinations of the specific embodiments described herein.
As used herein, the phrase "and/or," when used in a list of two or more items, means that any one of the listed items can be employed alone or any combination of two or more of the listed items can be employed. For example, if a composition is described as comprising or not comprising components a, B and/or C, the composition may or may not comprise: only A; only B; only C; a and B in combination; a and C in combination; b and C in combination; or a combination of A, B and C.
The present description also uses numerical ranges to quantify certain parameters relating to various embodiments of the invention. It should be understood that when numerical ranges are provided, such ranges are to be construed as: literal support is provided for purported limits that only list the lower value of the range, as well as the purported limits that only list the upper value of the range. For example, a disclosed numerical range of about 10 to about 100 provides literal support for an assertion reciting "greater than about 10" (without an upper bound) and an assertion reciting "less than about 100" (without a lower bound).
As used herein, a pharmaceutically acceptable salt of a therapeutic compound in relation to the present invention means a salt of a pharmaceutically acceptable compound, i.e., a salt that can be used to prepare pharmaceutical compositions, which are generally safe, non-toxic and neither biologically nor otherwise undesirable, and which are acceptable for human pharmaceutical use, and which possess a desired degree of pharmacological activity. Such pharmaceutically acceptable salts include those with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or addition salts with organic acids such as 1, 2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, 2-naphthalenesulfonic acid, 3-phenylpropionic acid, 4' -methylenebis (3-hydroxy-2-ene-1-carboxylic acid), 4-methylbicyclo [2.2.2] oct-2-ene-1-carboxylic acid, acetic acid, aliphatic monocarboxylic and dicarboxylic acids, aliphatic sulfuric acid, aromatic sulfuric acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, carbonic acid, cinnamic acid, citric acid, cyclopentanepropionic acid, ethanesulfonic acid, fumaric acid, meglumine acid (glucetacinacid), gluconic acid, glutamic acid, glycolic acid, heptanoic acid, hexanoic acid, hydroxynaphthoic acid, lactic acid, lauryl sulfuric acid, maleic acid, malic acid, malonic acid, manidola acid (Mandela acid), methanesulfonic acid, muconic acid, o- (4-hydroxybenzoyl) benzoic acid, oxalic acid, p-chlorobenzenesulfonic acid, phenyl-substituted alkanoic acid, propionic acid, p-toluenesulfonic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, tartaric acid, tert-butylacetic acid, trimethylacetic acid, and the like. Pharmaceutically acceptable salts also include base addition salts which may be formed when an acidic proton present is capable of reacting with an inorganic or organic base. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide, and calcium hydroxide. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like. It should be recognized that the particular anion or cation forming part of any salt of the present invention is not critical so long as the salt as a whole is pharmacologically acceptable. Additional examples of pharmaceutically acceptable Salts and methods of their preparation and Use are presented in Handbook of Pharmaceutical Salts Properties, and Use, p.h.stahl & c.g.wermuth eds., ISBN 978-3-90639-058-1 (2008).
In preparing the compounds of the present invention, starting components of relatively high purity should be used, typically at least about 90% pure by weight, and more preferably at least about 98% pure by weight. Naturally occurring sources of ingredients are often unsuitable or undesirable because these naturally occurring products may contain relatively small amounts of the desired components and/or have potentially interfering compounds therein. Furthermore, the use of low purity ingredients generally results in little or no compound according to the invention.
Accordingly, preferred starting compounds or components of the present invention are synthetically derived or derived from one or more naturally occurring products that have been substantially modified to contain at least about 90% by weight (more preferably at least about 98% by weight) of the desired component. As used herein, "synthetically derived" means that the component in question is synthesized using the particular starting ingredients and one or more chemical and/or biological reactions to obtain a substantially pure compound. Modification of naturally occurring products may include extraction or any other physical or chemical step to obtain the desired end product.
As used herein, the terms "alkyl," "alkenyl," "alkynyl" mean and are intended to encompass straight chain, branched chain and cyclic groups. "amine" means and is intended to encompass primary, secondary, and tertiary amines. "thio group" means and is intended to encompass thiols, sulfides, disulfides, and sulfoxides. "derivative" means and is intended to encompass compounds, moieties, and/or groups substituted with an atom, group, or side chain that does not substantially degrade (e.g., degrade no more than about 20%, preferably no more than about 10%) the properties of the compound, moiety, or group as compared to the unsubstituted version thereof.
As indicated, certain preferred compounds or agents of the present invention comprise a pair of fused polycyclic moieties, each fused polycyclic moiety comprising an N-containing ring, wherein the fused polycyclic moieties are joined or connected by a single tether or linker moiety, shown schematically as
PCM1—L—PCM2
Wherein PCM1 and PCM2 are fused polycyclic moieties (which may be the same or different), wherein L is a tether or linker. As the schematic indicates, linker L may be attached to PCM1 and PCM2 at any position on any loop thereof, and the bonding sites of both PCM1 and PCM2 need not be the same. Fused polycyclic and linker moieties are described below.
Fused polycyclic compounds or moieties
The fused polycyclic moieties of the invention are derived or synthesized from starting components, which result in compounds or moieties having the following general structure:
wherein one of the terminal rings is a 6-membered ring, the 6-membered ring including at least one N heteroatom located at one or more positions around the 6-membered ring as allowed by any valency (the single N atom shown in structure I is merely exemplary in terms of the position of the N atom and the number of N atoms). The 6-membered ring may be aryl (e.g., pyrido ring) or non-aryl (e.g., piperidine ring) in nature, or contain multiple N atoms (e.g., piperazine ring). Further, with respect to structure I, RG1 is fused to the terminal 6-membered N-containing ring and has 5-8 atoms (as used herein, "fused" refers to the fact that the fused rings share 2 adjacent atoms or, in other words, 1 covalent bond). Ring RG2 can be absent (i.e., the moiety is bicyclic), and if present, ring RG2 is fused to ring RG1 and the terminal six-membered ring and has 5-8 atoms. In the RG1, RG2 (if present) and six-membered N-containing rings, in each case the majority of the ring atoms are carbon atoms. However, these rings may also include one or more heteroatoms, such as S, O or N.
The internal dotted lines shown in RG1 and RG2 represent the fact that a single ring may have one or more double bonds and may be aromatic or non-aromatic in nature. As shown, in a six-membered N atom-containing ring, one or more N atoms may be located at any permissible position around the ring, and the dashed line indicates that the six-membered ring may have 1,2 or 3 double bonds. The N subscript on each Y1 represents the fact that there may be single or multiple substituents at any permissible position or positions around the six-membered N-atom containing ring RG1 and/or RG 2; preferably, each n is independently 1,2 or 3. Y1 and Y2 are each independently selected from the group consisting of: -absent, OH, C1-C12 (preferably C1-C4) alkyl, alkenyl and alkynyl groups, C1-C12 (preferably C1-C4) alkoxy and alkoxyphenyl groups, aryl and aryloxy groups, aldehyde and formaldehyde groups, amines, nitro groups, nitrile groups, C2-C6 carboxylic acid groups, boronic acid groups, sulphur groups and amino acids, wherein any of the above mentioned may be substituted by N, S, O, B or halogen atoms.
<xnotran> I , , -2- ,6- -2- ,2- -4- ,4- -7- ,8- , ,8- ,5- -3- ,4- -N- ,1- ,7- ,6,7- -2,4- ,6- ,1- ,4- ,8- , ,8- -5- , N- ,6- ,2- -3- ,5- ,2,6- ,3- ,2- -6- ,6- ,8- , -4- ,6- ,7- ,6- , ,4- ,8- ,3- -2- -4- ,6- ,3- ,2- -4- ,2,4- ,1- ,7- -2- , </xnotran> 1-methyl-3, 4-dihydroisoquinoline, 4-methyl-6H, 7H-thieno [3,2-c ] pyridine, 7-methyl-4H, 5H-thieno [2,3-c ] pyridine, 1-ethyl-3, 4-dihydroisoquinoline, 5-methyl-7, 8-dihydro-1, 6-naphthyridine, 1, 4-dimethyl-3, 4-dihydro-2, 7-naphthyridine, 5-methyl-7, 8-dihydro-1, 6-naphthyridine, and 4-methyl-6, 7-dihydrothieno [3,2-c ] pyridine.
Various fused tricyclic compounds corresponding to moieties according to structure I are also useful in the present invention. One class of fused tricyclic compounds are beta-carboline compounds and derivatives thereof having a tricyclic ring system, e.g., a bicyclic ring consisting of a six-membered benzene ring and a fused five-membered pyrrole ring, wherein the terminal N-containing ring is fused to the intermediate pyrrole ring. Exemplary beta-carbolines include tryptoline, abietic hydrocarbons (pinoline), harmine (harmane), harmine, hamalin, tetrahydrohamalin, and 9-methyl-beta-carboline. In some cases hamalin is preferred for use in the present invention.
Hamalin (7-methoxy-1-1-methyl-4, 9-dihydro-3H-pyrido [3,4-b ] indole) is a fluorescent psychoactive alkaloid from the group of Peganum harmala alkaloids and β -carbolines and is present in various plants, such as Peganum harmala. Hamalin is identified as CAS #304-21-2 and exists in two tautomeric forms:
as used herein, "hamalin" refers to one or two tautomers. Other hamalin components are described below.
Some of the hamalin components have structures
Wherein the numbered 6-membered fused ring is an N-heterocycle having a single N atom at any of positions 2-5, and the R6' substituent may be located at any ring position; r5' is H, OH, C1-C12 (preferably C1-C4) alkoxy, aryloxy (e.g. benzyloxy or phenoxy), carboxy, biphenyl, nitro, carboxylate; and R6' is H, OH, C1-C12 (preferably C1-C4) alkyl or C1-C12 (preferably C1-C4) carboxylic acid.
Representative compounds of this class include hamalin and the following:
in the above representative compounds, any methoxy substituent may be replaced by a C2-C4 alkoxy group or a phenoxy group.
Linker compounds and moieties
Each linker L provides two bonding branches from a single atom forming at least part of the linker moiety. Thus, the linker moiety may assume an effective "V" or "Y" configuration in which a single atom is located at the lower vertex (as depicted in structure II below), with two linking branches each bonded to a fused polycyclic moiety. Thus, the linker may be a single methylene group (CH 2) in which a fused polycyclic moiety is bonded to a carbon atom of the methylene group to assume an effective "V" configuration. In a similar manner, the linker may include a pair of alkyl groups having an intermediate carbon atom, such as CH3-C-CH3, such that the fused polycyclic moiety is bonded to the intermediate carbon atom. Thus, preferred linkers include multiple atoms, one of which is a bonding atom of a fused polycyclic moiety. The single bond atoms of the linker may be selected from non-metallic, and in particular, carbon, nitrogen, oxygen, fluorine, phosphorus, sulfur, chlorine, bromine, and iodine atoms. Metal atoms, such as Pt, are generally less preferred. Furthermore, the bond between the individual atoms and the bonding branches may be a classical covalent bond, meaning that each atom participating in the bond contributes at least one electron as part of a molecular orbital. However, typical metal bonding, such as coordinate bonding or dative bonding, is generally less desirable.
It will be appreciated that the linker compound or moiety serves to isolate the fused polycyclic moiety forming part of the compounds of the invention, and may also contribute to the morphological and/or steric characteristics of the complete compound. As used herein, and consistent with conventional linker nomenclature, the entirety of any polyatomic linker moiety between fused polycyclic moieties is considered a "linker" without any manual separation of such polyatomic linker moieties, wherein one atom of the linker moiety is considered a "linker" and the remainder of the linker moiety is not considered part of a "linker". For example, if a propyl moiety is used as a linker moiety, wherein two fused polycyclic moieties are each bonded to a terminal carbon of the propyl moiety, it is not suitable and not consistent with the present invention to consider one of the terminal CH 2s of the methylene group as a linker while ignoring the presence of the remaining CH2-CH2 groups as part of the linker.
In certain preferred compounds of the invention, the fused tricyclic moiety is bonded to the linker through a single atom, and wherein this single atom is a carbon atom of a methine group. The vocabulary of Organic Chemistry schemes (illuminated gloss of Organic Chemistry) defines a "methine group" as a part of the molecular structure corresponding to methane minus three hydrogen atoms, i.e., a CH group. The methine group is in contrast to a "methylene group" or CH2 group, which is defined as a portion of the molecular structure corresponding to methane minus two hydrogen atoms.
Some linker moieties may be derived from aldehydes in which both of the fused polycyclic moieties are bonded to the carbonyl carbon of the aldehyde functionality, thereby assuming an effective "Y" configuration. In certain embodiments, suitable aldehyde linker moieties are characterized by a six-membered ring having an attached aldehyde functionality, which is structurally as follows.
Wherein the substituents may be located at any position around the ring. R1' is a C1-C12 (preferably C1-C4) aldehyde, and R2' -R5' is independently and selectively selected from the group consisting of: H. OH, C1-C12 (preferably C1-C4) alkyl groups, C2-C12 (preferably C2-C5) alkenyl groups, C1-C12 (preferably C1-C4) alkoxy groups, C1-C12 (preferably C1-C4) aldehyde groups, acetate groups, isobutyrate groups, phenyl groups, phenoxy groups, benzyloxy groups, C2-C12 (preferably C2-C6) alkyl esters, halogens (e.g., F, br, I, cl), primary and secondary amines, nitro groups and mixtures thereof. The dashed bond in the six-membered ring indicates that the six-membered ring can be cyclohexane, or have one, two, or three carbon-carbon double bonds (e.g., cyclohexene, cyclohexadiene, phenyl or derivatives thereof).
Representative compounds of this class include vanillin, benzaldehyde, cinnamaldehyde, cuminaldehyde, o-vanillin, perillaldehyde, cyclohexane carboxaldehyde, and the following:
still additional phenylaldehydes useful as linkers in the present invention include the following moieties: 2-methoxybenzaldehyde, 3-ethoxy-4-hydroxybenzaldehyde, 4-formyl-2-methoxyphenyl isobutyrate, 3, 4-dimethoxybenzaldehyde, 4-hydroxy-3-methoxy-5-nitrobenzaldehyde, 4-formyl-2-methoxyphenyl acetate, 3-hydroxy-5-methoxybenzaldehyde, 2-hydroxy-4-methoxybenzaldehyde, 3-chloro-4-hydroxy-5-methoxybenzaldehyde, 4- (benzyloxy) -3-methoxybenzaldehyde, 3-hydroxy-4, 5-dimethoxybenzaldehyde, 3-bromo-4-hydroxy-5-methoxybenzaldehyde, 2-bromo-3-hydroxy-4-methoxybenzaldehyde, 3-hydroxy-2-iodo-4-methoxybenzaldehyde, 3-methoxybenzaldehyde, 3-phenoxybenzaldehyde, 4-phenoxybenzaldehyde, [1,1' -biphenyl ] -3-formaldehyde, 4-fluoro-3-phenoxybenzaldehyde, 3-fluorobenzaldehyde, 4-fluorobenzaldehyde, 3, 5-difluorobenzaldehyde, 2,4, 5-trifluorobenzaldehyde, 2,3,4,5, 6-pentafluorobenzaldehyde, 4-methylbenzaldehyde, terephthalaldehyde, 4-chlorobenzaldehyde, 4- (prop-1-en-2-yl) cyclohex-1-ene-1-carbaldehyde, 4-isopropylbenzaldehyde and cyclohexanecarboxaldehyde.
In other embodiments, aliphatic or alkenyl aldehydes may be used as linkers. Typically, such linkers are part of aldehydes, such as C1-C12 alkyl or C2-C12 alkenyl aldehydes, and include representative compounds such as (E) -hex-2-enal (C6H 10O, accurate mass: 98.07), 3-methylbutanal (isovaleraldehyde) (C5H 10O, accurate mass: 86.07), 3, 7-dimethyloct-6-enal (citronellal) (C10H 18O, accurate mass: 154.14), 7-hydroxy-3, 7-dimethyloctanal (hydroxycitronellal) (C10H 20O2, accurate mass: 172.15), and lauraldehyde (C12H 24O, accurate mass: 184.18).
Complete compounds of the invention
As previously mentioned, one general form of the compounds is set forth in the schematic
PCM1—L—PCM2。
Preferred materials for this representation are listed in Structure II below
Therein it can be seen that an intermediate tether or linker L is bonded to the six-membered N-containing ring of the corresponding fused polycyclic moiety of structure I, and in particular to the single atom forming the lower vertex and at least a portion of linker L. The bonding site of the linker L to the fused polycyclic moiety may be located at any permissible position around the six-membered ring, including at the N-heteroatom (in which case Y2 would not be present), and such bonding sites need not be the same for the respective polycyclic moieties. The six-membered terminal N-containing ring, RG1, RG2, Y1, and Y2 substituents, and the values of N are those previously defined for structure I.
One class of compounds (structure III below) has a central linker bonded to the N-containing B ring at a corresponding position at the ortho-carbon atom relative to the nitrogen atom, where each β -carboline group may be independently substituted or unsubstituted. With respect to the first moiety ring and the β -carboline group, "substituted" means that they can be substituted at any position (and independently in the case of the respective β -carboline group) with any substituent that does not substantially degrade (e.g., degrade no more than about 20%, preferably no more than about 10%) the properties of the compound compared to its unsubstituted version.
More particularly, certain other such compounds have the general structure III:
wherein each of X1, X2, X3 and X9 is independently selected from the group consisting of: -OH, C1-C12 alkyl, alkenyl and alkynyl groups, C1-C12 alkoxy and alkoxyphenyl groups, aryl and aryloxy groups, aldehyde and formaldehyde groups, amines, nitro groups, nitrile groups, C2-C6 carboxylic acid groups, boronic acid groups, sulphur groups and amino acids, wherein any of the above mentioned may be substituted by N, S, O, B or halogen atoms, Z comprises the above mentioned single bonding atom and is selected from the group consisting of: C1-C12 alkyl, alkenyl and alkynyl groups, C1-C12 alkoxy and alkoxyphenyl groups, aryl and aryloxy groups, aldehyde and formaldehyde groups, amines, nitro groups, nitrile groups, C2-C6 carboxylic acid groups, boronic acid groups, sulfur groups and amino acids, wherein any of the above mentioned may be substituted by N, S, O, B or halogen atoms. Each X3 may be attached at any position around the corresponding terminal phenyl moiety of the β -carboline group. Each Y is independently absent (e.g., there is a direct bond between the two B rings, or Z may be directly coupled to one or both of the B rings), H, OH, C1-C12 (preferably C1-C4) alkyl, alkenyl, and alkynyl groups, C1-C12 (preferably C1-C4) alkoxy, and alkoxyphenyl groups, aryl, and aryloxy groups, aldehyde groupsA group, an amine, a nitro group, a nitrile group, a C2-C6 carboxylic acid group, a boronic acid group, a sulfur group and an amino acid, wherein any of the above mentioned may be substituted by N, S, O, B or a halogen atom. Preferably, Y is a C1-C12 (preferably C1-C4) group consisting of C, CH and/or CH2 atoms or groups, and Z is C, CH or CH 2. X9 is preferably selected from the group consisting of: absent (e.g., M may be bonded to Z), C1-C12 (preferably C1-C4) alkyl groups, and C2-C12 (preferably C2-C5) alkenyl groups. M is selected from the group consisting of: structure IIIA, absent, OH, C1-C12 (preferably C1-C4) alkyl, alkenyl and alkynyl groups, C1-C12 (preferably C1-C4) alkoxy and alkoxyphenyl groups, aryl and aryloxy groups, aldehyde groups, amines, nitro groups, nitrile groups, C2-C6 carboxylic acid groups, boronic acid groups, sulphur groups and amino acids, wherein any of the above mentioned may be substituted by N, S, O, B or halogen atoms. Each X4, X5, X6, X7 and X8 of structure IIIA is attached at any position around the a ring and is independently selected from the group consisting of: -OH, C1-C12 (preferably C1-C4) alkyl, alkenyl and alkynyl groups, C1-C12 (preferably C1-C4) alkoxy and alkoxyphenyl groups, aryl and aryloxy groups, aldehyde groups, amines, nitro groups, nitrile groups, C2-C6 carboxylic acid groups, boronic acid groups, sulphur groups and amino acids, any of the above mentioned being substitutable by N, S, O, B or halogen atoms. Labels in the A RingRefers to the fact that 0, 1,2, or 3 double bonds may optionally be present (e.g., the A ring may be cyclohexane, cyclohexene, cyclohexadiene, benzene or derivatives thereof), and wherein markers attached to both B rings->Refers to the fact that the following may optionally be present: 1) One or two non-fused double bonds located at one or two valency allowed positions around either or both of the B rings, such as in figures a-d below; 2) The double bond between either or both of the B rings and Y or Z, with or without an additional non-fused bis at any valency-permitting position around the corresponding N-containing ringKeys, such as the following figures e-g. In the case of 2), when there is a double bond between any one of the N-containing ring nitrogen atoms and Y or Z, X1 may be absent, such as in FIGS. a-c and g. However, if there is no such nitrogen double bond, the corresponding X1 is as defined above and is preferably selected from the group consisting of: H. OH and C1-C12 (preferably C1-C4) alkyl groups, such as in FIGS. d-f; or 3) either or both of the B rings do not contain non-fused double bonds, and each X1 is as described above, and is preferably selected from the group consisting of: H. OH and C1-C12 (more preferably C1-C4) alkyl groups.
In the preferred case where Z is a methine CH group, X9 is not absent or H.
Listed below are diagrams depicting certain exemplary double bond configurations of either or both of the B rings of structure III above.
Advantageously, each X1 is absent, each X2 is H, and each X3 is methoxy.
In certain embodiments of structure III, M is a 1A ring, both X1 are absent, both X3 are methoxy, 2 of X4, X5, X6, X7, and X8 are H, and at least one of X4, X5, X6, X7, and X8 is selected from the group consisting of: H. -OH, methoxy, ethoxy, phenoxy, C2-C5 alkenyl groups, F and Cl with the proviso that: 1) When one or more of X4, X5, X6, X7 and X8 is F or Cl, the remainder of X4, X5, X6, X7 and X8 is H; 2) Only one of X4, X5, X6, X7 and X8 may be phenoxy, and in such a case, the remainder of X4, X5, X6, X7 and X8 is H.
In other embodiments, certain compounds are provided that comprise two hamalin moieties and a single phenyl moiety derived from a phenylaldehyde compound, having the general structure IV:
wherein X10 is-CH = CH-, X11, X12, X13 and X14 are each independently selected from the group consisting of: H. -OH, methoxy, ethoxy and phenoxy, F and Cl, with the proviso that: 1) At least one of X12, X13 or X14 is H; 2) When one or more of X11, X12, X13 or X14 is F or Cl, the remainder of X11, X12, X13 and X14 is H; 3) Phenoxy groups are present only at X12 and X11, X13 and X14 are all H, and 4) if methoxy or ethoxy is present, at least one such methoxy or ethoxy must be located at the 2 or 3 position, wherein the label attached to the two N-containing ringsRefers to the fact that the following may optionally be present: 1) One or two non-fused double bonds located at one or two valency allowed positions around either or both of the N-containing rings, such as in figures a-c below; 2) Double bonds between either or both of the N-containing rings and adjacent carbon atoms, with or without additional non-fused double bonds at any valency-allowed position around the corresponding N-containing ring, such as in graph g below; or 3) either or both of the N-containing rings do not contain non-fused double bonds, and each X1 is independently selected from the group consisting of: H. OH and C1-C12 (preferably C1-C4) alkyl groups.
When X10 is absent and X11, X12, X13 and X14 are all H, the resulting structure is the compound 560 described in example 12; when X10 is absent, X11 is H, X12 is methoxy, X13 is-OH, and X14 is H, the resulting structure is the 562 compound described in example 14; when X10 is absent, X11 is-OH, X12 is methoxy, and X13 and X14 are both H, the resulting structure is the following primary 523 compound; when X10 is absent, X11, X13 and X14 are all H, and X12 is phenoxy, the resulting structure is the compound 594 described in example 24; and when X10 is-CH = CH-, and X11, X12, X13, and X14 are all H, the resulting structure is 561 bis-hamartine compounds listed below as the main compounds of hamartine and cinnamaldehyde.
In other embodiments, certain compounds comprising two hamalin moieties and a single linker moiety within the scope of structure IV are provided. These compounds are selected from the group consisting of:
synthesis of the complete Compounds of the invention
In preparing the compounds of the present invention, starting components of relatively high purity should be used, typically at least about 90% pure by weight, and more preferably at least about 98% pure by weight. Naturally occurring sources of the use ingredients are often unsuitable or undesirable because these naturally occurring products may contain relatively small amounts of the desired components and/or have potentially interfering compounds therein. Furthermore, the use of low purity ingredients generally results in little or no compound according to the invention.
Accordingly, preferred starting compounds or components of the present invention are synthetically derived or derived from one or more naturally occurring products that have been substantially modified to contain at least about 90% by weight (more preferably at least about 98% by weight) of the desired component. As used herein, "synthetically derived" means that the component in question is synthesized using the particular starting ingredients and one or more chemical and/or biological reactions to obtain a substantially pure compound. Modification of naturally occurring products may include extraction or any other physical or chemical step to obtain the desired end product.
One method of preparing the compounds of the present invention, particularly where the linker moiety is derived from an aldehyde, involves a direct reaction between the aldehyde and the fused polycyclic compound of interest. Thus, the product produced by this method is the reaction product of an aldehyde and a fused polycyclic compound.
In carrying out the aldehyde reaction between any type of aldehyde and the one or more fused polycyclic compounds, the weight ratio of the one or more aldehyde components to the one or more fused polycyclic compounds in the reaction mixture should range from about 0.5 to 25, more preferably from about 0.7 to 1 to 6, and most preferably from about 1.5. In terms of weight amounts, the amount of the one or more aldehyde components should range from about 25 to 95% by weight, and the weight amount of the one or more fused polycyclic compounds should range from about 5 to 75% by weight, the total weight of these reactants being 100% by weight. In most cases, it is preferred that the weight amount of the one or more aldehyde components should be present in excess weight relative to the amount of the one or more fused polycyclic compounds.
These components are typically mixed with an organic solvent such as a C1-C4 lower alcohol (e.g., methanol, ethanol, or propanol) and/or dimethyl sulfoxide (DMSO) and allowed to stand at a temperature ranging from about 20-60 ℃ for a period of time at ambient pressure (typically about 12 hours-4 weeks). Alternatively, the mixture may be refluxed (e.g., in ethanol at 50-85 ℃ for 30 minutes-2 hours, or in methanol at 55 ℃ for 30 minutes). The reaction product may then be recovered in liquid or solid form. Depending on the solvent chosen, the reaction product may exhibit different colors, but this does not affect the anticancer properties of the reaction product. Furthermore, the particular reaction conditions are generally not critical.
The production of effective esters, metal complexes and pharmaceutically acceptable salts of the compounds is very simple and within the skill of the art. For example, salts may be formed by reacting the product with an inorganic or organic acid.
The above-mentioned reactants, reaction ratios, amounts of reactants and reaction conditions are applicable to all the aldehyde reactions according to the present invention, and the skilled artisan can easily determine the optimum conditions by routine experiments.
In some cases where an aldehyde reaction is used, it may be difficult to determine the precise structure or structures of the reaction product. However, the molecular weight of the active reaction product can be determined and this is an important criterion for the active product. Thus, the important reaction product of benzaldehyde and hamalin has a molecular weight of about 516, whereas such reaction product of vanillin and hamalin has a molecular weight of about 562. "about" in relation to the molecular weights referred to herein means the listed molecular weights plus or minus 5 weight units. In addition, the molecular weight of the reaction product derivatives (e.g., reduction products produced by hydrogenation, esters, or salts) may vary somewhat; but such weights are easily calculated based on the nature of the derivative. Thus, the preferred molecular weights described herein are for the non-derivatized versions of the reaction products.
The second synthetic method can be used when it is desired to produce fused tricyclic compounds such as beta-carbolines and their derivatives. Generally, this method involves reacting an indolealkylamine with a diacid to form an intermediate, followed by a ring closure reaction to form the final compound of interest.
A third reaction method is shown below, particularly for producing compounds having a fused bicyclic moiety bonded to a linker moiety.
Benzaldehyde/hamalin 560 compounds
Benzaldehyde is a benzene ring with aldehyde substituents and is the main component of bitter almond oil. It is identified by CAS # 100-52-7.
The aldehyde reaction between benzaldehyde and hamalin is preferably carried out by mixing the two components together in a weight ratio of about 2:1 (benzaldehyde: hamalin). Ethanol is then added to give a final reaction mixture concentration of about 10 mg/mL, more preferably about 700 mg/mL to form a dispersion. The vial is then capped and the mixture in the vial is allowed to stand in a warm water bath at about 50 ℃ (more broadly, about 40-60 ℃) for about 3 days (more broadly, about 1-10 days). The solid compound was then washed with water and methanol to give the final product in about 90-95% purity by weight.
Some compounds are formed from a hamalin moiety and a benzaldehyde moiety, one of which has a molecular weight of about 320. Other products also have a hamalin moiety and a benzaldehyde, but have a molecular weight of about 302 due to the loss of water associated with the reaction. These products are listed below.
In addition, useful compounds are formed from two hamalin moieties and a single linker moiety derived from benzaldehyde, with a molecular weight of about 516, as follows.
Other compounds containing one benzaldehyde moiety and two hamalin moieties include the following.
As explained in example 12, the identified compound is
Analogs of the above compounds have a molecular weight of 520.68 and are reduced versions in which the nitrogen atoms of the two hamalin moieties are hydrogenated, eliminating the double bond therein, as listed below:
more broadly, however, suitable benzaldehyde/hamartor compounds include one or more of the following: the structure is as follows:
and dimers, isomers, and tautomers thereof, wherein the-O-R3 group can be independently located at any position on the terminal phenyl group, wherein each R1 is independently selected from the group consisting of: absent, H, OH, C1-C12 (preferably C1-C4) alkyl groups and halogens (such as I and Br), each R2 is independently selected from the group consisting of: H. OH and C1-C12 (preferably C1-C4) alkyl groups and halogens (such as I and Br), each R3 group being independently selected from the group consisting of: a C1-C12 (preferably C1-C4) alkyl group and a substituted or unsubstituted phenyl group, and wherein the symbolsRefers to the fact that the following may optionally be present: 1) One or two non-fused double bonds located at one or two valency-allowed positions around either or both six-membered N-containing rings, such as in figures a-d below; 2) The double bond between either or both of the N-containing rings and the adjacent carbon of the central moiety, with or without additional non-fused double bonds at any valency-allowed position around the corresponding N-containing ring, such as in figures e-g. In the case of 2) a double bond between any one of the N-containing ring nitrogen atoms and its adjacent carbon atom, R1 is absent, such as in FIGS. a-c and g. However, if there is no such nitrogen double bond, then the corresponding R1 is selected from the group consisting of: H. OH and C1-C12 (preferably C1-C4) alkyl groups, such as in FIGS. d-f; or 3) either or both of the B rings do not contain non-fused double bonds, and each R1 is independently selected from the group consisting of: H. OH and C1-C12 (preferably C1-C4) alkyl groups.
Listed below are diagrams depicting certain exemplary double bond configurations of either or both of the N-containing rings of structure V.
In other embodiments, the following compounds are useful
Wherein R7 and R8 are attached at any position around the phenyl ring and are independently selected from the group consisting of: H. OH and a C1-C12 (preferably C1-C4) alkoxy group, and wherein preferably R7 is OH and R8 is a C1-C12 (preferably C1-C4) alkoxy group.
Cinnamic aldehyde/hamalin 561 compounds
Cinnamaldehyde exists in the bark of the cinnamon tree and exists in cis and trans isomers. It is identified by CAS # 104-55-2.
These compounds are produced using an aldehyde reaction in the same manner as the benzaldehyde/hamalin product using an aldehyde reaction and have molecular weights of about 346, 328 and 542 as shown below. The MW542 compound includes a first cinnamaldehyde moiety, where two hamalin moieties are bonded to the first moiety. The MW346 compound is composed of a single cinnamaldehyde moiety and a single hamalin moiety, while the MW 328 product is a dehydrated version of the MW346 product. The major compound is the MW542 product.
Mainly:
likewise, analogs of the above primary structures are hydrogenated versions in which the N atoms of both hamalin moieties are hydrogenated, eliminating the double bond therein.
More broadly, however, suitable cinnamaldehyde/hamarelin compounds include one or more of the following: the structure is as follows:
and dimers, isomers, and tautomers thereof, wherein the-O-R3 group can be independently located at any position on the terminal phenyl group, wherein each R1 is independently selected from the group consisting of: absent, H, OH and C1-C12 (preferably C1-C4) alkyl groups, each R2 is independently selected from the group consisting of: H. OH and C1-C12 (preferably C1-C4) alkyl groups, each R3 group being independently selected from the group consisting of: a C1-C12 (preferably C1-C4) alkyl group and a substituted or unsubstituted phenyl group, and wherein the symbolsRefers to the fact that the following may optionally be present: 1) One or two non-fused double bonds located at one or two valency-allowed positions around either or both six-membered N-containing rings, such as in figures a-d below; 2) The double bond between either or both of the N-containing rings and the adjacent carbon of the central moiety, with or without additional non-fused double bonds at any valency-allowed position around the corresponding N-containing ring, such as in figures e-g. In the case of 2) a double bond between any one of the N-containing ring nitrogen atoms and its adjacent carbon atom, R1 is absent, such as in FIGS. a-c and g. However, if there is no such nitrogen double bond, then the corresponding R1 is selected from the group consisting of: H. OH and C1-C12 (preferably C1-C4) alkyl groups, such as shown in FIGS. d-f; or 3) either or both of the N-containing rings do not contain non-fused double bonds, and each R1 is independently selected from the group consisting of: H. OH and C1-C12 (preferably C1-C4) alkyl groups.
Listed below are diagrams depicting certain exemplary double bond configurations of either or both N-containing rings of structure VI.
Vanillin/hamalin 562 compound
The aldehyde reaction between the vanillin and hamalin components proceeds in the same manner as the benzaldehyde/hamalin reaction, resulting in the products listed below.
As explained in example 14, the identified vanillin/hamalin compound is
Analogs of the above structure involve hydrogenation of the nitrogen atom of the N-containing ring and are listed below:
more broadly, however, suitable vanillin/hamalin compounds include one or more of the following: the structure is as follows:
and dimers, isomers and tautomers thereof, wherein each R4 is independently selected from the group consisting of: absent, H, OH and C1-C12 (preferably C1-C4) alkyl groups, each R5 is independently selected from the group consisting of: H. OH and C1-C12 (preferably C1-C4) alkyl groups, each R6 group being independently located at any position around the respective terminal phenyl group, or at either of the two open positions of the two N-containing rings, and being selected from the group consisting of: C1-C12 (preferably C1-C4) alkoxy group, H, OH and substituted or unsubstituted phenyl group, R7 and R8 are attached at any position around the phenyl ring and are independently selected from the group consisting ofA group consisting of: H. OH and a C1-C12 (preferably C1-C4) alkoxy group, with the proviso that R7 and R8 are not both H, and wherein, preferably, R7 is OH, R8 is a C1-C12 (preferably C1-C4) alkoxy group, and each R9 is independently selected from the group consisting of: H. OH and C1-C12 (preferably C1-C4) alkyl groups, and wherein the labelRefers to the fact that the following may optionally be present: 1) Zero, one, or two non-fused double bonds, located at one or two valency-allowed positions around either or both six-membered N-containing rings, such as in figures a '-d'; 2) The double bond between either or both of the N-containing rings and the adjacent carbon of the central moiety, with or without additional non-fused double bonds at any valency-allowed position around the corresponding N-containing ring, such as in figures e '-g' below. In the case of 2) a double bond between any one of the N-containing ring nitrogen atoms and its adjacent carbon atom, R4 is absent, such as in figures a ' -c ' and g ' below. However, if there is no such nitrogen double bond, then the corresponding R4 is selected from the group consisting of: H. OH and C1-C12 (preferably C1-C4) alkyl groups, such as in FIG. d '-f'; or 3) either or both of the N-containing rings do not contain non-fused double bonds, and each R4 is independently selected from the group consisting of: H. OH and C1-C12 (preferably C1-C4) alkyl groups.
Listed below are diagrams depicting certain exemplary double bond configurations of either or both N-containing rings of structure VII.
Exemplary compounds consistent with 3) above are hydrogenated versions of the preferred 562 compounds having the structure
Phenoxybenzaldehyde/hamalin 594 compound
As described in example 24, the main 594 compound has the following structure:
o-vanillin/hamalin 523 compounds
The aldehyde reaction between o-vanillin and hamalin is very diverse and the resulting product is likewise variable. Four reaction schemes have been identified as potential candidates, as listed below.
It will be observed that the compounds of scheme 4 above involve coupling between hamalin and o-vanillin via a pyrrole nitrogen linkage, i.e. the o-vanillin moiety is bonded to the nitrogen atom forming part of the pyrrole ring of hamalin.
The initial aldehyde reaction between O-vanillin and hamalin of scheme 1 can also yield the following compound having the chemical formula C21H20N2O3 and a molecular weight of 348.15. It will be observed that in this case the initial reaction between o-vanillin and hamalin takes place at the cyclohexyldiene nitrogen atom.
Preferred o-vanillin/damalin compounds have the structure:
more broadly, however, preferred o-vanillin/di-hamalin compounds are defined by the following structure VIII:
and dimers, isomers, and tautomers thereof, wherein the-O-R3 group can be independently located at any position on the terminal phenyl group, wherein each R1 is independently selected from the group consisting of: absent, H, OH and C1-C12 (preferably C1-C4) alkyl groups, each R2 is independently selected from the group consisting of: H. OH and C1-C12 (preferably C1-C4) alkyl groups, each R3 group being independently selected from the group consisting of: a C1-C12 (preferably C1-C4) alkyl group and a substituted or unsubstituted phenyl group, and wherein the symbolsRefers to the fact that the following may optionally be present: 1) One or two non-fused double bonds located at one or two valency-allowed positions around either or both of the six-membered N-containing rings, such as in figures a-d below; 2) The double bond between either or both of the N-containing rings and the adjacent carbon of the central moiety, with or without additional non-fused double bonds at any valency-allowed position around the corresponding N-containing ring, such as in figures e-g. In the case of 2) a double bond between any one of the N-containing ring nitrogen atoms and its adjacent carbon atom, R1 is absent, such as in FIGS. a-c and g. However, if there is no such nitrogen double bond, the corresponding R1 is selected from the group consisting ofGroup (b): H. OH and C1-C12 (preferably C1-C4) alkyl groups, such as in FIGS. d-f; or 3) either or both of the N-containing rings do not contain non-fused double bonds, and each R1 is independently selected from the group consisting of: H. OH and C1-C12 (preferably C1-C4) alkyl groups.
Listed below are diagrams depicting certain exemplary double bond configurations of either or both N-containing rings of structure VI.
One particular aldehyde reaction for the preparation of o-vanillin-hamalin compounds is to mix together solid microparticles of o-vanillin and hamalin in a weight ratio of o-vanillin to hamalin of about 2. The dispersion was then stirred and allowed to stand at room temperature for 24 hours. The method comprises the following specific steps: (1) Mixing 500mg o-vanillin and 250mg hamalin together in a 15mL bottle; (2) Gently shake the vial until a homogeneous powder mixture appears; (3) adding 10mL of ethanol and/or DMSO to the dry mixture; (4) stirring with a vortex mixer at 1000rpm for 10 minutes; and (5) allowing the dispersion to stand, and the reaction was performed at room temperature for 24 hours.
A similar technique involving the reaction between hamalin and vanillin involves mixing together particulate hamalin and vanillin in a weight ratio of about 2. The mixture was then allowed to stand at 50 ℃ for about 3 days. A bluish solid formed which was filtered and washed with methanol and recovered.
Phenoxybenzaldehyde/hamalin 594 compound
The aldehyde reaction between the phenoxybenzaldehyde and hamalin components proceeds in the same manner as the benzaldehyde/hamalin reaction, resulting in the products listed below.
And dimers, isomers, and tautomers thereof, wherein the-O-R3 group can be independently located at any position on the terminal phenyl group, wherein each R1 is independently selected from the group consisting of: absent, H, OH and C1-C12 (preferably C1-C4) alkyl groups, each R2 is independently selected from the group consisting of: H. OH and C1-C12 (preferably C1-C4) alkyl groups, each R3 group being independently selected from the group consisting of: a C1-C12 (preferably C1-C4) alkyl group and a substituted or unsubstituted phenyl group, and the phenoxy group may be substituted at any position on the benzyl ring, and wherein the labelRefers to the fact that the following may optionally be present: 1) One or two non-fused double bonds located at one or two valency-allowed positions around either or both six-membered N-containing rings, such as in figures a-d below; or 2) double bonds between either or both of the N-containing rings and adjacent carbons of the central moiety, with or without additional non-fused double bonds at any valency-allowed positions around the corresponding N-containing ring, such as in panels e-g. In the case of 2) a double bond between any one of the N-containing ring nitrogen atoms and its adjacent carbon atom, R1 is absent, such as in figures a-c and g. However, if there is no such nitrogen double bond, then the corresponding R1 is selected from the group consisting of: H. OH and C1-C12 (preferably C1-C4) alkyl groups, such as in FIGS. d-f; or 3) either or both of the N-containing rings do not contain non-fused double bonds, and each R1 is independently selected from the group consisting of: H. OH and C1-C12 (preferably C1-C4) alkyl groups.
Listed below are diagrams depicting certain exemplary double bond configurations of either or both of the N-containing rings of structure VII.
Particularly preferred compounds of this type are listed below and with reference to example 24 wherein 3-phenoxybenzaldehyde is used.
Hamamelin component
Some of the hamalin components are tricyclic compounds of this structure
Wherein the numbered 6-membered fused ring is an N-heterocycle having a single N atom at any of positions 2-5, and the R6 substituent may be located at any ring position; r5' is H or C1-C12 (preferably C1-C4) alkoxy; and R6' is H, C1-C12 (preferably C1-C4) alkyl or C1-C12 (preferably C1-C4) carboxylic acid.
Representative compounds of this class include hamalin and the following:
harmol hydrochloride dihydrate
In the above representative compounds, any methoxy substituent may be replaced by a C2-C4 alkoxy group or a phenoxy group.
In addition to those described above and detailed in the examples below, many other aldehydes have been reacted with hamalin to produce compounds. In each case, the reaction was carried out by mixing 500mg of aldehyde and 250mg of hamalin together in a 15mL bottle, then gently shaking the bottle until a homogeneous powder mixture was present. Thus, 10mL of ethanol was added to the dry mixture, the bottle was capped, and placed in a warm water bath at about 40 ℃ for about 24 hours.
In the following table, specific hamalin-reactive aldehydes are identified along with the compounds obtained. In the latter case, the composition of each compound is determined by the portion of the reactants therein minus any dehydration and/or reduction due to reaction, and its approximate molecular weight. For example, a given compound referred to as "H + A-H2O" refers to a product comprising one hamalin moiety and one aldehyde moiety, minus one water molecule, while 2H + A-H20-2H refers to a product comprising two hamalin moieties, one aldehyde moiety, one water atom less, and two hydrogen atoms less.
The following are representative structures of some of the compounds listed in the above table, in which two hamalin moieties are reacted with the listed aldehydes (in some cases, the aldehydes are identified by different equivalent names).
1,1' - (2- (2-methoxyphenyl) propane-1, 3-diyl) bis (7-methoxy-4, 9-dihydro-3H-pyrido [3,4-b ] indole) C34H34N4O 3-methoxybenzaldehyde, O-anisaldehyde
4- (1, 3-bis (7-methoxy-4, 9-dihydro-3H-pyrido [3,4-b ] indol-1-yl) propan-2-yl) -2-ethoxyphenol C35H36N4O 4-ethoxy-4-hydroxybenzaldehyde, ethyl vanillin
4- (1, 3-bis (7-methoxy-4, 9-dihydro-3H-pyrido [3,4-b ] indol-1-yl) propan-2-yl) -2-methoxyphenyl isobutyrate C38H40N4O 5-formyl-2-methoxyphenyl isobutyrate, vanillin isobutyrate
1,1' - (2- (3, 4-dimethoxyphenyl) propane-1, 3-diyl) bis (7-methoxy-4, 9-dihydro-3H-pyrido [3,4-b ] indole) C35H36N4O 43, 4-dimethoxybenzaldehyde, veratraldehyde
4- (1, 3-bis (7-methoxy-4, 9-dihydro-3H-pyrido [3,4-b ] indol-1-yl) propan-2-yl) -2-methoxy-6-nitrophenol C34H33N5O 6-hydroxy-3-methoxy-5-nitrobenzaldehyde, 5-nitrovanillin
4- (1, 3-bis (7-methoxy-4, 9-dihydro-3H-pyrido [3,4-b ] indol-1-yl) propan-2-yl) -2-methoxyphenylacetate C36H36N4O 5-formyl-2-methoxyphenylacetate, vanillin acetate
3- (1, 3-bis (7-methoxy-4, 9-dihydro-3H-pyrido [3,4-b ] indol-1-yl) propan-2-yl) -5-methoxyphenol C34H34N4O 4-hydroxy-5-methoxybenzaldehyde
2- (1, 3-bis (7-methoxy-4, 9-dihydro-3H-pyrido [3,4-b ] indol-1-yl) propan-2-yl) -5-methoxyphenol C34H34N4O 4-hydroxy-4-methoxybenzaldehyde
4- (1, 3-bis (7-methoxy-4, 9-dihydro-3H-pyrido [3,4-b ] indol-1-yl) propan-2-yl) -2-chloro-6-methoxyphenol C34H33ClN4O 3-chloro-4-hydroxy-5-methoxybenzaldehyde
1,1' - (2- (4- (benzyloxy) -3-methoxyphenyl) propane-1, 3-diyl) bis (7-methoxy-4, 9-dihydro-3H-pyrido [3,4-b ] indole) C41H40N4O 4-benzyloxy-3-methoxybenzaldehyde
5- (1, 3-bis (7-methoxy-4, 9-dihydro-3H-pyrido [3,4-b ] indol-1-yl) propan-2-yl) -2, 3-dimethoxyphenol C35H36N4O 5-hydroxy-4, 5-dimethoxybenzaldehyde, 3, 4-dimethoxy-5-hydroxybenzaldehyde
4- (1, 3-bis (7-methoxy-4, 9-dihydro-3H-pyrido [3,4-b ] indol-1-yl) propan-2-yl) -2-bromo-6-methoxyphenol C34H33BrN4O 4-bromo-4-hydroxy-5-methoxybenzaldehyde, 5-bromovanillin
3- (1, 3-bis (7-methoxy-4, 9-dihydro-3H-pyrido [3,4-b ] indol-1-yl) propan-2-yl) -2-bromo-6-methoxyphenol C34H33BrN4O 4-bromo-3-hydroxy-4-methoxybenzaldehyde
3- (1, 3-bis (7-methoxy-4, 9-dihydro-3H-pyrido [3,4-b ] indol-1-yl) propan-2-yl) -2-iodo-6-methoxyphenol C34H33IN4O 4-hydroxy-2-iodo-4-methoxybenzaldehyde
1,1' - (2- (3-methoxyphenyl) propane-1, 3-diyl) bis (7-methoxy-4, 9-dihydro-3H-pyrido [3,4-b ] indole) C34H34N4O 3-methoxybenzaldehyde, m-anisaldehyde
1,1' - (2- (3-phenoxyphenyl) propane-1, 3-diyl) bis (7-methoxy-4, 9-dihydro-3H-pyrido [3,4-b ] indole) C39H36N4O 3-phenoxybenzaldehyde
1,1' - (2- (4-phenoxyphenyl) propane-1, 3-diyl) bis (7-methoxy-4, 9-dihydro-3H-pyrido [3,4-b ] indole) C39H36N4O 3-phenoxybenzaldehyde
1,1'- (2- ([ 1, 1-biphenyl ] -3-yl) propane-1, 3-diyl) bis (7-methoxy-4, 9-dihydro-3H-pyrido [3,4-b ] indole) C39H36N4O2[1,1' -biphenyl ] -3-carbaldehyde, biphenyl-3-carbaldehyde
1,1' - (2- (4-fluoro-3-phenoxyphenyl) propane-1, 3-diyl) bis (7-methoxy-4, 9-dihydro-3H-pyrido [3,4-b ] indole) C39H35FN4O 3-fluoro-3-phenoxybenzaldehyde
1,1' - (2- (3-fluorophenyl) propane-1, 3-diyl) bis (7-methoxy-4, 9-dihydro-3H-pyrido [3,4-b ] indole) C33H31FN4O 2-fluorobenzaldehyde
1,1' - (2- (4-fluorophenyl) propane-1, 3-diyl) bis (7-methoxy-4, 9-dihydro-3H-pyrido [3,4-b ] indole) C33H31FN4O 2-fluorobenzaldehyde
1,1' - (2- (3, 5-difluorophenyl) propane-1, 3-diyl) bis (7-methoxy-4, 9-dihydro-3H-pyrido [3,4-b ] indole) C33H30F2N4O 23, 5-difluorobenzaldehyde
1,1' - (2, 4, 5-trifluorophenyl) propane-1, 3-diyl) bis (7-methoxy-4, 9-dihydro-3H-pyrido [3,4-b ] indole) C33H29F3N4O2, 4, 5-trifluorobenzaldehyde
1,1' - (2- (perfluorophenyl) propane-1, 3-diyl) bis (7-methoxy-4, 9-dihydro-3H-pyrido [3,4-b ] indole) C33H27F5N4O2, 3,4,5, 6-pentafluorobenzaldehyde
1,1' - (2- (p-tolyl) propane-1, 3-diyl) bis (7-methoxy-4, 9-dihydro-3H-pyrido [3,4-b ] indole) C34H34N4O 2-methylbenzaldehyde
4- (1, 3-bis (7-methoxy-4, 9-dihydro-3H-pyrido [3,4-b ] indol-1-yl) propan-2-yl) benzaldehyde C34H32N4O3 terephthalaldehyde
1,1' - (2- (4-chlorophenyl) propane-1, 3-diyl) bis (7-methoxy-4, 9-dihydro-3H-pyrido [3,4-b ] indole) C33H31ClN4O 2-chlorobenzaldehyde
1,1' - (2- (4- (prop-1-en-2-yl) cyclohex-1-en-1-yl) propan-1, 3-diyl) bis (7-methoxy-4, 9-dihydro-3H-pyrido [3,4-b ] indole) C36H40N4O 24- (prop-1-en-2-yl) cyclohex-1-ene-1-carbaldehyde, perillaldehyde
1,1' - (2- (4-isopropylphenyl) propane-1, 3-diyl) bis (7-methoxy-4, 9-dihydro-3H-pyrido [3,4-b ] indole) C36H38N4O 2-isopropylbenzaldehyde, cuminaldehyde
1,1' - (2-Cyclohexylpropane-1, 3-diyl) bis (7-methoxy-4, 9-dihydro-3H-pyrido [3,4-b ] indole) C33H38N4O2 cyclohexanecarboxaldehyde
1,1' - (2-isobutylpropane-1, 3-diyl) bis (7-methoxy-4, 9-dihydro-3H-pyrido [3,4-b ] indole) C31H36N4O2 exact mass: 496.28
Furthermore, many hamartoid compounds, in addition to those detailed in the examples below, react with different aldehydes to produce compounds. In each case, the reaction was carried out by mixing together 500mg of the selected aldehyde and 250mg of the hamalin-like compound in a 15mL vial, then gently shaking the vial until there was a homogeneous mixture of powders. Thus, 10mL of ethanol was added to the dry mixture, the bottle was capped, and placed in a warm water bath at about 40 ℃ for about 24 hours.
In the following table, specific hamaline-like compounds and aldehydes are identified along with the compounds obtained. In the latter case, the composition of each compound is determined by the portion of the reactants therein minus any dehydration due to the reaction, and its approximate molecular weight. For example, a given compound referred to as "H + a-H2O" refers to a product comprising a hamartlike compound moiety and an aldehyde moiety, minus one water molecule.
1=1,2,3, 4-tetrahydro-9H-pyrido [3,4-b ] indole (TH. Beta.C)
2= -6-methoxy-1-methyl-3, 4-dihydro-2H-pyrido [3,4-b ] indole (6-methoxy hami blue)
3=4, 9-dihydro-3H-beta-carbolin-1-ylmethyl ether
4= 6-methoxy-1, 2,3, 4-tetrahydro-9H-pyrido [3,4-b ] indole (abietic hydrocarbon)
5=2,3,4,5-tetrahydro-8-methoxy-1H-pyrido [4,3-b ] indole
6=4, 9-dihydro-1-methyl-3H-pyrido [3,4-b ] indole-7-ol hydrochloride (harmol hydrochloride)
Examples
The following examples illustrate preferred therapeutic agents and methods according to the present invention, but it is understood that these examples are given by way of illustration only, and nothing therein should be taken as a limitation on the overall scope of the invention.
Example 1
In this example, a series of 523 compounds were prepared using an aldehyde reaction, including reacting respective amounts of solid synthetic o-vanillin (99% purity by weight) and synthetic hamalin (92% purity by weight). In each case, o-vanillin and hamalin react to produce one or more compounds. These compositions are designated GZ523.001-008 and their compositions and formulations are listed below, with the amounts and approximate weight percent levels of these two components:
GZ523.001-294mg o-vanillin (85.5%) +50mg hamalin (14.5%), mixed immediately with 5mL ethanol;
GZ 523.002-294 mg o-vanillin (85.5%) +50mg hamalin (14.5%), mixed immediately with 5ml dmso;
GZ523.003-229.3mg o-vanillin (66.7%) +114.7mg hamalin (33.3%) as dry ingredients were mixed together and left to stand in a closed container for 48 hours, then 5mL ethanol was added;
GZ523.004-286.7mg o-vanillin (83.3%) +57.3mg hamalin (16.7%) as dry ingredients were mixed together and left for 13 days, then 5mL ethanol was added;
GZ523.005-229.3mg o-vanillin (66.7%) +114.7mg hamalin (33.3%), with 5mL DMSO, mix immediately and stand for 24 hours;
GZ523.006-229.3mg o-vanillin (66.7%) +114.7mg hamalin (33.3%), mixed immediately with 5mL ethanol and left to stand for 24 hours;
GZ523.007-172mg o-vanillin (50%) +172mg hamalin (50%), mixed immediately with 5mL ethanol and left to stand for about 3 weeks; and
GZ523.008-229.3mg o-vanillin (66.7%) +114.7mg hamalin (33.3%) as dry ingredients were mixed together and placed in a closed vial for 45 minutes and then allowed to stand in a tray with a lid for 24 hours before adding 5mL ethanol.
Example 2
A series of identical in vitro assays were performed on the 523 compound of example 1 against lymphoma (MO 205) and leukemia (jurkat E6-1) cell lines to determine the anti-cancer properties of the composition, as determined by cell death. The protocol for the assay is given below.
Method
Individual cells were grown in suspension in culture medium (RPMI supplemented with 10% FBS), maintained at about 500,000 cells/mL. Cells were plated directly in 96-well plates and each well was exposed to increasing doses of GZ523.001-.008 composition for 24 hours (a minimum of 4 replicates per dose). PrestoBlue (Life Technologies, inc) was added to each well 24 hours after exposure to the selected dose of test composition, and fluorescence readings were taken after 4-6 hours using a microplate reader (enspiremutimode, perkinElmer) at an excitation wavelength of 485nm and an emission wavelength of 560 nm. Results were averaged after background subtraction and normalized to untreated cell controls.
The results of these tests are set forth in figures 1-16, where figures 1-8 are lymphoma test results and figures 9-16 are leukemia test results, and in each case, the compositions exhibit excellent anti-cancer activity at relatively low doses. In general, doses in excess of 10 μ g/mL give very good results, with doses in excess of about 40 μ g/mL giving extraordinary results.
Example 3
In this example, a 523 compound comprising o-vanillin and hamalin in a weight ratio of 2. The reaction was dispersed in ethanol to reach a concentration of 75mg/mL and allowed to react for a period of 24 hours. After completion of the reaction, the compound (designated GZ523F 001) was treated by HPLC to recover a high molecular weight fraction consisting predominantly (about 70% by weight) of one or more di-oligomers having a molecular weight of about 696 and unreacted hamalin. These di-oligomers include one or more compounds exemplified by the dimer of scheme 1.
The compound was then tested against the same lymphoma and leukemia cells as listed in example 2. The results of this test are set forth in fig. 17 and 18. These results confirm that these compounds exhibit very significant anticancer activity.
Example 4
In this series of tests, the susceptibility of non-hodgkin's lymphoma to the preferred compound according to the invention, namely GZ523.006 described in example 1, was tested. Cell lines were grown in suspension according to the supplier's instructions and tested by the method described in example 2, except that it was not repeated. The following table lists the subtype, cell line ID number and half effective dose (EC) for each non-Hodgkin lymphoma tested 50 )。EC 50 Represents the potency of the GZ523.006 composition on cell lines and ranges from 8-38 μ g/mL, which is considered to be a therapeutically suitable dosage range. The magnitude of the effect of the highest concentration of GZ523.006 determines how effective the composition is in killing the corresponding cells directly. For all cell lines tested, 100% of the cancer cells died at doses of 25 μ g/mL or greater.
TABLE 1
Example 5
In this example, 562 compounds were prepared by mixing 500mg vanillin powder and 250mg hamalin powder in a 15mL bottle. The powder was gently shaken to form a substantially homogeneous mixture and 10mL of dimethyl sulfoxide was added. The mixture was then stirred with a vortex mixer at 1000rpm for 10 minutes to form a dispersion. In the case of one composition (GZ 518.000), one or more dispersion compounds were tested against lymphoma (MO 205) immediately by application to cells as described in example 2. A second composition (GZ 518.001) was prepared from this dispersion by allowing it to react for 24 hours at room temperature before testing against lymphoma cells by application to the cells. As listed in figures 19 and 20, both compositions exhibited good anti-cancer properties.
Example 6
In this example, the EC of GZ523.006 was determined for 25 different lymphoma cell lines 50 The value is obtained. Two using GZ523.006 between 0.4 and 100 μ g/mLExperiments were performed with multiple serial dilutions. Test wells were prepared for background subtraction using media and GZ523.006 control. Each cell line was seeded with 10,000 cells/well and three technical replicates were performed. After 96 hours of exposure, alamar Blue reagent (Life Technologies) was added to each well and incubated for one hour at 37 ℃. Fluorescence values were recorded using a 560nm excitation/590 nm emission filter set and EC calculated using GraphPadprism software 50 And (4) concentration. EC for 25 cell lines tested 50 The data are listed in fig. 21, where: GCB-DLBCL is a germinal center B cell diffuse large B cell lymphoma cell line; ABC-DLBCL is an activated B-cell diffuse large B-cell lymphoma cell line; MCL is mantle cell lymphoma cell line; and FL is a follicular lymphoma cell line. Error bars represent standard error of the mean.
Each cell line of FIG. 21 was incubated with 5, 10 or 20. Mu.g/mL for 72 hours, followed by incubation of Hoechst 33342 dye (BD Pharmingen) at 37 ℃ for 60 minutes. Cells were washed twice and fluorescence data was collected using a LSRII 4-laser flow cytometer (BD Biosciences). The data were analyzed using the Flojo v10 and Modfit v4.05 software to quantify the percentage of dead cells (sub-G1), senescent cells (G1 peak) and periodic cells (S phase and G2) in each case. Table 2 summarizes the data from this series of tests.
TABLE 2
Annexin V and 7-AAD staining were used, and the BD apoptosis detection kit (BDPharmingen) was used to query the mechanism of GZ523.0006 cell death. Four cell lines showing high sensitivity to GZ523.006 were selected. The cell lines were incubated with 5, 10 or 20 μ g/mL GZ523.006 for 72 hours, washed, resuspended in 1 Xannexin V binding buffer, and stained with PE Annexin V and 7-AAD for 15 minutes at room temperature in the dark. Cells were then suspended in additional binding buffer and analyzed using a LSRII 4-layer flow cytometer (BD Biosciences). Data were analyzed using Flojo v10 by gating untreated cells. A summary of the results of this experiment are shown in table 3.
The Caspace 3/7 assay was performed by inducing apoptosis using a luminescence-based Caspace cleavage assay. Cells were plated at 10,000 cells per well and exposed to 20 μ g/mL GZ523.006 for 48 hours. Caspace activation was measured using the Caspace Glo 3/7 assay (Promega) and compared to a loading body control exposure. Caspace activation was measured with three technical replicates and two experimental replicates using a light panel reader. The results of these tests are summarized in fig. 22, where bar 1 is the control and bar 2 is the treated cells. Error bars represent standard error of the mean. These tests demonstrated that GZ523.006 exhibits cytotoxic properties on lymphoma cell lines to induce apoptosis. Mantle cell lymphoma cell lines exhibited the highest resistance, while diffuse large B-cell lymphoma of germinal center B-cell-like subtype exhibited the greatest sensitivity.
Example 7
1 purpose
The objective of this study was to determine the maximum tolerated dose and potential toxicity of GZ523.010 after 7 days of daily oral administration in CD1 mice. GZ523.010 was prepared by mixing 2433mg o-vanillin, 1217mg hamalin and 5mL ethanol. The mixture was then sonicated at 35 ℃ for one hour to ensure complete mixing, and then allowed to stand at room temperature for 24 hours.
2 overview of the study
There were four dose groups consisting of negative carrier control group and 3 dose groups, and the oral gavage was repeated with 10 mice/sex/group for 7 days. Animals were dosed with GZ523.010 once daily and euthanized on study day 8. All animals were observed daily for any clinical signs after dosing. A total necropsy was performed for each animal and all available samples were clinically pathologically performed at termination. The first day of dosing was defined as study day 1. Study design and evaluation variables are presented in tables 4 and 5.
TABLE 4
Design of research
TABLE 5
Variables and intervals evaluated
Parameter(s) | Spacer |
Observation of mortality | Twice daily |
Physical examination | Once in the adaptation process |
Body weight | Daily life |
Consumption of food | Daily (group mean value) |
Clinical observations | Twice daily |
Clinical pathology | Three animals per sex per group available hematology, coagulation and serum chemistry |
Gross necropsy | All animals retained a complete tissue list for future analysis |
3 materials and methods
3.1GZ523.010
Test/control item name: | GZ523.010 | distilled water |
Lot/batch number: | 20160530.1500 | S1277 |
storage conditions were as follows: | 4-8℃ | at room temperature |
The manufacturer: | NA (sponsor) | Southern Beverage Packers |
The components are as follows: | 730mg/mL GZ523.010 in ethanol | Water (W) |
3.2 test System
3.2.1 animals, housing and environmental conditions
3.2.2 diet and Water
3.3 dosing procedure
All animals were dosed once daily by oral gavage for 7 days according to table 4. Dose volume was calculated based on the most recent body weight. Food and water were provided throughout the study period.
3.4 mortality/moribund status
General in-cage observations were made of mortality/moribundity status twice daily.
3.5 physical examination
During acclimation, the qualified personnel performed a physical examination of all study animals to determine study eligibility and again prior to termination. The examination includes, but is not limited to, examination of the skin and outer ear, eye, abdomen, nerves, behavior, and general physical condition.
3.6 clinical observations
Detailed clinical observations were performed twice daily. The animals were observed for any signs of disease or response to treatment. A record of the appearance, change or disappearance of clinical signs was kept on the clinical observation table for each individual observation time point.
3.7 body weight and food consumption
All study animals were weighed daily during the-1 st to 8 th day termination period. Group average food consumption was recorded daily from day-1 to day 7.
3.8 termination and autopsy
All animals were euthanized with CO2 at termination. Each animal was necropsied and all assigned questions/organs were collected for potential future analysis. The following tissues (if present) were preserved in 10% neutral buffered formalin except testis and eye. Testis is fixed in modified Davidson's solution and eye in Davidson's solution. The collected tissue was saved for further evaluation.
* The person performing the necropsy may decide to collect the macroscopic lesions at his or her discretion.
3.9 clinical Pathology
Clinical pathology was performed at termination. Clinical pathology analysis was performed on all assigned animals that were euthanized as planned. Animals were fasted overnight.
Serum chemistry: when available, blood samples (-0.5 mL) were collected from three study animals per sex per group and allowed to clot for 15 minutes at room temperature. No anticoagulant was used. Serum samples were prepared by centrifugation at 3000RPM for 15 minutes. Serum chemistry preferably includes (√). When the samples are not sufficient for analysis, several samples of the same set are pooled together:
blood coagulation: blood samples (-0.4 mL/animal) were collected from three study animals per sex per group when available. Sodium citrate (3.2%) was used as an anticoagulant. Plasma was prepared by centrifugation at 3000rpm for approximately 15 minutes at 4 ℃. Blood coagulation assays include, but are not limited to:
and (3) hematology analysis: blood samples (-0.4 mL) were collected from three study animals per sex per group when available. K3-EDTA was used as an anticoagulant. Hematological analyses include (priority (√) for:
4 results
4.1 dosing
Table 6 summarizes the dosing. All study animals were successfully dosed with the target amount of the carrier or test article formulation. All dosage formulations are prepared prior to dosing. Before the preparation of the dosage formulation, it was observed that the stock test article (730 mg/mL) was not of uniform consistency. Therefore, a dosage concentration of 100mg/mL cannot be formulated due to the large amount of precipitate. The protocol was modified to reduce the dose concentration. The stock formulation was warmed to room temperature and vigorously stirred with sonication to achieve a uniform (paste-like) consistency. It was then diluted to 73mg/mL with ethanol (secondary stock). Secondary reserves were used to prepare each final dosage formulation. The final consistency of the dosage formulation appears to be a suspension and is mixed well prior to administration.
TABLE 6
Dosing-actual dose level summary
a One mouse (1F17;
b one mouse was identified as male at termination (suspected of being misidentified at transit).
4.2 mortality/moribund status
No mortality or severe moribund was observed during the study period.
4.3 physical examination
All study animals were subjected to one physical examination by the veterinarian during acclimation and again prior to termination. All animals were overall healthy and considered suitable for inclusion in the study.
4.4 clinical observations
Clinical observations are listed in table 7. There were no findings associated with the test article during the exposure period following daily oral gavage dosing.
TABLE 7
Summary of group clinical observations
4.5 body weight
The results of the summary of body weights and body weight changes are presented in tables 8 and 9. During the course of the study, most study animals gained weight generally, especially in males. Female body weight remained or slightly decreased and there was no significant difference between groups.
TABLE 8
Weight results summary of the group (g)
a One mouse (1F17. b Animals were fasted overnight.
TABLE 9
Conclusion of the results of the body weight Change (g/day)
a One mouse (1F17.
b Animals were fasted overnight.
4.6 food consumption
Summary of group food consumption results are presented in table 10. During the course of the study, study animals usually had similar food consumption. Overall, there were no significant differences between the groups.
TABLE 10
Group food consumption summary (g/day)
a Food consumed before fasting.
4.7 clinical Pathology
Blood samples were collected from euthanized mice for hematology and serum chemistry analysis. Some blood samples (serum) do not have sufficient volume to complete all target parameter analysis.
The hematology and coagulation data are summarized in table 11. Neither the hematologic nor coagulation parameters appeared to be affected in mice treated with different dose levels of test article when compared to the control group (group 1).
Table 12 summarizes the serum chemistry data. All serum chemistry results were within the normal range. None of the serum chemistry parameters appeared to be affected in mice treated with different dose levels of the test article preparation when compared to the control group (group 1).
TABLE 11
Group mean hematology and coagulation at termination
TABLE 12
Group mean serum chemistry at termination
"indicating insufficient sample volume
4.8 autopsy and tissue Collection
A full necropsy was performed on all study animals. Autopsy included examination of the external surface, all orifices, as well as the cranium, thorax, abdomen, and pelvic cavities, including the contents. Macroscopic findings are summarized in table 13. All findings were considered incidental and not related to test article administration. All tissues, including all remaining cadavers, were collected and fixed for future potential evaluation.
Watch 13
Individual animal autopsy findings
5 summarisation and conclusion
This study was conducted to determine the maximum tolerated dose and potential toxicity of test articles in CD1 mice after 7 days of daily oral administration. There were four dose groups consisting of negative vector control group and 3 dose groups. The oral gavage dose was repeated at 10 mice/sex/group for 7 days of dosing treatment. All animals were successfully dosed once daily as recommended and euthanized on study day 8. All animals were observed daily for any clinical signs after dosing. A total necropsy was performed for each animal and all available samples were clinically pathologically performed at termination.
During the study period, there were no unplanned deaths and no significant moribund status was observed. Overall, all animals had normal food consumption and weight gain as expected during the study. There were no clinical findings associated with the test article. Clinical pathology analysis and autopsy at termination showed that all study animals were in a normal state.
In summary, animals tolerated doses of GZ523.010 up to 300 mg/kg/day via daily oral administration for 7 days. Under the study conditions, no adverse effect was observed and the level (NOAEL) was determined to be 300 mg/kg/day.
Example 8
In this example, an in vitro cell proliferation assay was performed using: (1) human myeloma tumor cell lines; (2) human lymphoma tumor cell lines; (3) a solid human tumor cell line; and (4) parental, lenalidomide (Lenalidomide) resistant and bortezomib resistant Jeko-1 suite of cell lymphoma tumor cell lines. The compounds tested were three Eramalin compounds, 518B562 (or 562 for short), 560 and 561. In addition, a monohamalin product designated 518F014 was also tested. The monohamalin product has the following structure:
the 518B562 compound was prepared by: particulate hamamalin was mixed together with vanillin at a weight ratio of about 2. The mixture was then allowed to stand at 50 ℃ for about 3 days. A bluish solid formed which was filtered and washed with methanol and recovered. It was found that the addition of an acid such as hydrochloric acid to lower the pH of the product increased its solubility.
560 the compound was prepared by: 500mg benzaldehyde and 250mg hamalin were mixed together in a 15mL bottle and then shaken. 10mL of DSMO was then added to the mixture, which was then stirred using a vortex mixer at 1000rpm for 10 minutes. The vortexed mixture was then allowed to stand at room temperature for 24 hours. The product was obtained as an orange liquid containing 10.6mM of compound and stored at 4 ℃ until use.
561 the compound was prepared by: 500mg of cinnamaldehyde and 250mg of hamalin were mixed together in a 15mL bottle and then shaken. 10mL of DSMO was then added to the mixture, which was then stirred using a vortex mixer at 1000rpm for 10 minutes. The vortexed mixture was then allowed to stand at room temperature for 24 hours. The product was obtained as an orange solid dispersed in a liquid containing 10mM of compound and stored at 4 ℃ until use.
Each proliferation assay was performed as follows. Test cells were plated in growth medium using 384-well microtiter plates in a volume of 50 μ Ι _. Cells were incubated in a humidified incubator at 37 ℃ for 24 hours. After 24 hours of incubation, test compounds were added to the test wells in DSMO solvent at concentrations ranging from 0.0075-100 μ M. Control wells received an equal volume of DSMO without compound. After dosing, the cells were incubated for 72 hours in a humidified incubator at 37 ℃. After this exposure, sterile water and CellTiter-100 μ L of 1. The plates were then incubated at room temperature for 60 minutes and the luminescence of each well was then recorded using a luminometer as a measure of cell proliferation.
Table 14 below lists the cell lines, IC's, tested using the respective compounds 50 Summary of results and identification of the corresponding graphical plots for each assay.
This data shows that preferred 560, 561 and 562 bis-hamalin compounds have significant potency compared to mono-hamalin 518F014 compoundSignificantly lower IC 50 The value is obtained. This phenomenon was found to be consistent throughout the test compounds of the present invention, i.e., the di-hamstring compounds are significantly superior compared to the mono-hamstring compounds.
Example 9
In this example, a compound mixture was prepared by reacting 2 parts by weight of hamalin and 3-phenoxybenzaldehyde (3-phenoxybenzaldehyde: hamalin). The reaction mixture had three components, namely fractions with molecular weights 608 (47% by weight), 788 (32% by weight) and 394 (21% by weight). The MW 608 product comprises two hamalin moieties and one 3-phenoxybenzaldehyde, wherein one water molecule is removed; the MW 788 product comprises two hamalin moieties and two 3-phenoxybenzaldehyde moieties, wherein two water molecules are removed; and MW 394 product contains one mole each of hamalin and 3-phenoxybenzaldehyde, with one water molecule removed. The following table lists the results of a series of assays performed on 31 different cell lines using this compound mixture, where the assays were performed as outlined in example 2. IC was performed twice in each case 50 Tested and the results averaged to give an average IC 50 The value is obtained.
Example 10
In this example, pancreatic cancer cells (S2-007 and Mia-PaCa 2) were treated with compound 518B562, previously described, at various times and concentrations, and proliferation assays were then generated using the techniques described above. The product significantly inhibited cell proliferation at doses of 1-25 μ g/mL and in a 24-72 hour time-dependent manner. IC of Compounds on S2-007 and Mia-PaCa2 cells 72 hours after treatment 50 Values were determined to be 3. Mu.g/mL and 5. Mu.g/mL, respectively.
Example 11
In this example, a cluster map (clustergram)/heatmap of RNA sequences for Cancer Stem Cell (CSC) markers was performed before and after treatment of S2-007 human pancreatic cancer cells with 518B 562. The experiment was performed using Whole Transcriptome Shotgun Sequencing (WTSS) followed by bioinformatic data analysis of CSC markers. RNA sequences/heatmaps were generated to obtain genome-wide gene expression profiles of pancreatic cancer cells.
One sample of a pancreatic cancer cell line was untreated, while the same sample was treated with 5 ug/mL of 518B 562. The samples were compared for RNA sequence using the Illumina HISeq 2500 sequencer with a single read resolution of 100 bp. Sequence reads were mapped to the human genome (component grch38. Rel77) using STAR software (Dobin et al, 2012). Transcript abundance estimates were generated using Cufflinks software (Trapnell et al, 2010), and differential gene expression estimates were calculated using cuffdiffdiff software (Trapnell et al, 2013). The RNA sequence produced approximately 48.6 and 60.1 reads, with between 97.2% and 98.3% of the reads mapping to the reference genome.
The cluster or heatmap indicates that 518B562 significantly inhibits the gene cluster on the proliferation, anti-apoptosis and angiogenesis markers while upregulating the anti-proliferation and apoptosis markers. Specifically, 518B562 upregulate apoptosis markers [ ICAM5, WNK4, ALPP, LTRC26, SHBG, MT1X ] and antiproliferative markers [ NRP1, ATF2A, CYP1B1, ALPP, DEPTOR, MT1F ]. In addition, 518B562 down-regulated angiogenic markers [ OXTR, SYCP2, CRHR1, SPEG ], anti-apoptotic markers [ TUG1, FABP1, PI3, DOK5] and proliferation signaling markers [ FOXj1, SPP1, C3].
Example 12
6g benzaldehyde, 3g hamalin and 50mL ethanol were placed in a 250mL round bottom flask. The dispersion was refluxed at a temperature of about 78 ℃ for about 4 hours, after which it was allowed to cool gradually to room temperature. The resulting solid was collected by vacuum filtration, rinsed with approximately 200mL of cold water, and dried at room temperature to obtain a multiple twin racemic crystalline mass. A single domain is cut from one of the clusters and gives available diffraction data so that all hydrogen atoms can be located and modified to be independent isotropic atoms; the two nitrogen atoms also appear to be protonated. 560 the resulting two-dimensional structure of the compound was determined as:
the above structure is referred to herein as the "identified 560 compound".
Below is shown a three-dimensional representation of the above 560 compound, where the large circles represent carbon atoms and the small circles represent hydrogen atoms; the double bond is not shown in this representation. Furthermore, the hydrogen bond between nitrogen N1 and N4 is shown in dashed lines. It is believed that such hydrogen bonding may be important to the functionality of the compound. Other numbered atoms are provided for reference.
The above compounds can be subjected to isomerization, in particular during NMR analysis, to give the following two-dimensional isomeric structure:
the reduced form of any of the above isomers may be less prone to additional isomerization. The two-dimensional structure of the reduced compounds (produced by hydrogenation of the above compounds) is listed below.
Example 13
In this example, several 560 compounds were prepared by mixing together 6g benzaldehyde and 3g hamalin in a closed 40mL vial, followed by shaking for a few minutes. The closed vial was then placed in a 40 ℃ water bath for 1-5 days. After cooling, the vial was opened and placed in a Labconco Freezone 4.5L lyophilizer at 0.028kPa and-48 ℃ for 1 week. The contents of the vial were then mixed with a water/methanol combination and the resulting solid was collected by vacuum filtration. The molecular weights of the compounds were found to be 302, 320, 514 and 516.
Example 14
6g of vanillin, 3g of hamalin and 50mL of ethanol are placed in a 250mL round bottom flask. The dispersion was refluxed at a temperature of about 78 ℃ for about 4 hours, after which it was allowed to cool gradually to room temperature. The resulting solid was collected by vacuum filtration, rinsed with approximately 200mL of cold water, and dried at room temperature to obtain a multiple twin racemic crystalline mass. A single domain is cut from one of the clusters and gives available diffraction data so that all hydrogen atoms can be located and modified to be independent isotropic atoms; the two nitrogen atoms also appear to be protonated. The resulting two-dimensional structure of compound 562 was determined as:
example 15
In this example, two pancreatic cancer cells, S2-007 and MiaCaPa-2, were used to test the corresponding 560 and 562 compounds of examples 12 and 14 in a cell proliferation assay. In each assay, 5 × 10 4 Individual cells were seeded in 96-well culture plates. After 24 hours of incubation, cells were treated with different concentrations of 560 or 562 compounds and allowed to incubate for a further period of 72 hours. Cell proliferation values were determined by the enzyme hexosaminidase assay. The results of these tests are set forth in fig. 119 and 120 (560 compounds) and fig. 121 and 122 (562 compounds). These figures also provide IC50 values for each assay.
Example 16
In this example, 560 and 562 compounds of examples 12 and 14, respectively, were tested using a cell colony formation assay. 500 live S2-007 and MiaCaPa-2 cells were plated in six-well plates and allowed to grow for 24 hours. Cells were then incubated for 72 hours in the presence or absence of 560 and 562 compounds. The compound-containing medium was then removed and the cells were washed in PBS and incubated in complete medium for an additional 10 days. The resulting colonies were then washed in PBS and fixed with 10% formalin for 10 minutes at room temperature, then washed with PBS and stained with crystal violet. The control and compound supplemented determined colonies were then counted and compared.
FIG. 123 (560 compound, S2-007 cells) shows colony formation at 24, 48, and 72 hours for control (no 560 compound) and 4 μ g and 6 μ g of 560 compound. 560 compounds significantly perturbed colony formation, particularly at use levels of 6 μ g.
FIG. 124 (560 compound, miaPaCa-2 cells) shows colony formation at 24, 48, and 72 hours for control (no 560 compound) and 3 μ g and 5 μ g of 560 compound. 560 compound significantly perturbed colony formation at both use levels.
FIG. 125 (562 compounds, S2-007 cells) shows colony formation at 24, 48, and 72 hours for control (no 562 compounds) and 14 μ g and 16 μ g of 562 compounds.
FIG. 126 (562 compounds, S2-007 cells) shows colony formation at 24, 48, and 72 hours for control (no 562 compounds) and 20 μ g and 24 μ g of 562 compounds.
FIG. 127 (562 compound, miaPaCa-2 cells) shows colony formation at 24, 48, and 72 hours for control (no 562 compound) and 3 μ g, 7 μ g, 10 μ g, and 12 μ g of 562 compound. The 562 compound perturbed colony formation significantly, especially at higher use levels.
Example 17
In this example, 560 and 562 compounds of examples 12 and 14 were used in cell cycle tests against S2-07 and MiaPaCa02 cells, respectively. In each case, cells treated with 560 and 562 compounds for 72 hours were trypsinized and suspended in PBS. Single cell suspensions were fixed using pre-cooled 70% ethanol for 3 hours and then permeabilized with PBS containing 0.1% Triton X-100, 1mg/mL propidium iodide and 2mg RNase without DNase at room temperature. Flow cytometry assays were then performed using a fastalibur analyzer (Becton Dickinson), capturing 10,000 events per sample. The results were analyzed using ModFit LT TM software (version software House). These results were performed using a Sub G0 gated window that was alternately opened (with Sub G0) and closed (without Sub G0) to provide both resting and active cell data.
FIG. 128 and128A(Compound 560S2-007 cells) was shown inCell cycle results with and without Sub G0 at 24 and 48 hours.
FIG. 129 and129A(Compound 560MiaPaCa-2 cells) showed cell cycle results with and without Sub G0 at 24, 48 and 72 hours.
FIG. 130 and130A(Compound 562S2-007 cells) showed cell cycle results with and without Sub G0 at 24, 48 and 72 hours.
FIG. 131 and131A(Compound 562MiaPaCa-2 cells) showed cell cycle results with and without Sub G0 at 24, 48 and 72 hours.
Example 18
2200mg benzaldehyde plus 1100mg hamalin were placed in a 50mL beaker and mixed slightly. The beaker was heated for a few minutes until a color change was observed, and then the mixture was transferred to a 250mL round bottom flask with the aid of 50mL isopropanol. Next, 50. Mu.L of 37% HCl was added, and the mixture was refluxed for 1.5 hours. After about 1 hour, crystals began to form. After refluxing, the reaction mixture was allowed to stand and cool to ambient temperature and filtered using a buchner funnel, rinsing with cold isopropanol. The collected product weighed about 700mg and was red beet in color. Analysis of this compound showed that it contained approximately 18% of the identified 560 compound (mw = 516) and approximately 80% dimer (mw = 604).
Example 19
3000mg benzaldehyde plus 1500mg hamalin were placed in a 50mL beaker and mixed gently. The beaker was heated until the color of the mixture turned light brown. The mixture was then transferred to a 250mL round bottom flask with the aid of 30mL isopropanol. Next, 50. Mu.L of 37% HCl was added, and the mixture was refluxed for 30 minutes. After refluxing, the reaction mixture was allowed to stand and cool to ambient temperature and filtered using a buchner funnel, rinsing with cold isopropanol. The weight of the collected product was about 1325mg, which was yellow in color. Analysis of this compound showed that it contained approximately 80% of the identified 560 compound (mw = 516).
Example 20
8000mg of benzaldehyde plus 4000mg of hamalin were placed in a 50mL beaker and mixed slightly. The mixture was then transferred to a 250mL round bottom flask with the aid of 40mL methanol. Next, 50. Mu.L of 37% HCl was added, and the mixture was refluxed for 45 minutes. After refluxing, the reaction mixture was allowed to stand and cool overnight. After cooling, the mixture was filtered using a buchner funnel and rinsed with methanol. The product was yellow in color. Analysis of this compound showed that it contained approximately 93% of the identified 560 compound (mw = 516), with the remainder being unreacted hamalin.
Example 21
8000mg of vanillin plus 4000mg of hamalin were placed in a 50mL beaker. The mixture was heated by applying water at 40 ℃ to the outside of the beaker, which initiated the reaction and changed the color of the mixture from yellow to light brown. The mixture was then transferred to a 250mL round bottom flask with the aid of 50mL isopropanol to turn the mixture yellow-green. Once all the reactants dissolved, the color changed from yellow-green to yellow-brown. Next, 150. Mu.L of 37% HCl was added and heated until the mixture color became dark brown and a bluish precipitate was produced. The mixture was then refluxed for 25 minutes and the vessel was cooled using tap water. The reaction mixture was then filtered using a buchner funnel and rinsed with isopropanol. The mixture was then dried, producing a grayish blue color like gray. Analysis of this compound showed that it contained approximately 85% of the 562 compound of example 14 (mw = 562).
Example 22
4000mg of vanillin plus 2000mg of hamalin were placed in a 50mL beaker. The mixture was heated by applying water at 40 ℃ to the outside of the beaker, which initiated the reaction and changed the color of the mixture from yellow to dark brown. The mixture was then transferred to a 250mL round bottom flask with the aid of 50mL isopropanol. Once all the reactants dissolved, the color changed to dark reddish brown. Next, 500. Mu.L of 37% HCl was added and heated until the mixture color became dark brown and a bluish precipitate was produced. The mixture was then refluxed for 45 minutes and the vessel was cooled using tap water. The reaction mixture was then filtered using a buchner funnel and rinsed with isopropanol. The mixture was then dried to give about 1500mg of dark brown product. Analysis of this compound showed that it contained approximately 60% of the 562 compound of example 14 (mw = 562), approximately 23% of the anhydro adduct (mw = 348), and approximately 17% of the dimer (mw = 696).
Example 23
2g of cuminaldehyde, 1g of hamalin and 40mL of ethanol are placed in a 250mL round-bottom flask. The dispersion was refluxed at a temperature of about 65 ℃ for about 30 minutes, after which the mixture was allowed to cool gradually overnight to room temperature. The resulting bottoms liquid product was then analyzed. The main compound (referred to herein as the 561 product) has the following structure:
example 24
In this test, the relevant di-hamalin compound 594, di-hamalin 3-phenoxybenzaldehyde, was tested using the same cell line and procedure as described in example 8. 594 the structures of the compounds are listed below, and the cell proliferation assay data collected are given in the table below.
TABLE 16
As demonstrated by the above data, 594 compound was effective against a variety of cancer cells.
Example 25
In this example, in vitro cell proliferation assays were performed on different cell lines as described in example 8. In particular, cell lines are identified in table 17 below, and the tissue types are: a pancreas; the endometrium; triple Negative Breast Cancer (TNBC); non-small cell lung cancer (NSCLC); an ovary; renal Cell Carcinoma (RCC); cervical squamous cells; hemagglutinin and neuraminidase (H & N squamous cells); germinal center B cell-like new diffuse large B cell lymphoma (GCB-DLBCL); activated B cells-diffuse large B cell lymphoma (ABC-DLBCL); human myeloma; human myeloma cell line lymphoblastoid; infiltrating human myeloma cell line lymphocyte-like myeloma pleural effusion; human multiple myeloma; plasma cell leukemia/multiple myeloma Epstein-Barr nuclear antigen-negative (EBNA-negative) and expresses mRNA of the proto-oncogene B-cell lymphoma 2 (BCL 2); multiple myeloma from peripheral blood group IgD Lmabda.
According to the invention, these cell lines were tested with a series of two hamalaks/aldehyde compounds. The aldehydes reacted with hamalin are listed in Table 17 by numbers 1-2, 4-15, 17-24 and 27-30, and the corresponding compounds of like numbers are listed after Table 17. See below for details of the keys. Compounds were identified in the next section of table 17. In each case, the compounds were prepared by reacting one part by weight of hamalin and two parts by weight of aldehyde in ethanol at 50 ℃ overnight.
Key-tables 17-19
* The values were averaged using a 100. Mu.M test value
HMCL human myeloma cell line
HMCL-A human myeloma cell line lymphoblastoid
HMCL-B human myeloma cell line lymphocyte-like myeloma pleural effusion infiltration
(IgAk)
HMM human multiple myeloma
MM IgD is from multiple myeloma of peripheral blood group IgD lmabda
PCL/MM plasma cell leukemia/multiple myeloma EBNA-negative and expressed
mRNA of the prototype oncogene BCL2
SC squamous cell
TABLE 17
A compound:
# 1-O-anisaldehyde
# 2-Ethyl Vanillin
# 4-veratraldehyde
# 5-5-Nitro Vanillin
#6- -Vanillin acetate
# 7-3-hydroxy-4-methoxybenzaldehyde
# 8-2-hydroxy-4-methoxybenzaldehyde
# 9-3-chloro-4-hydroxy-5-methoxybenzaldehyde
# 10-3-benzyloxy-4-methoxybenzaldehyde
#11- -5-hydroxy-3, 4-dimethoxybenzaldehyde
#12- -5-Bromovanillin
# 13-2-bromo-3-hydroxy-4-methoxybenzaldehyde
#14- -3-hydroxy-2-iodo-4-methoxybenzaldehyde
# 15-m-anisaldehyde
#17- -4-Phenoxybenzaldehyde
# 18-Biphenyl-3-carbaldehyde
# 19-4-fluoro-3-phenoxybenzaldehyde
# 20-3-fluorobenzaldehyde
# 21-4-fluorobenzaldehyde
#22-3, 5-difluorobenzaldehyde
#23-2,4, 5-trifluorobenzaldehyde
#24
# 27-4-Chlorobenzaldehyde
# 28-Perilla aldehyde
#29- -cuminaldehyde
# 30-Cyclohexanecarboxaldehyde
Example 26
In this example, the compound was produced via the reaction between a fused bicyclic compound, i.e., 1-methyl-3, 4-dihydroisoquinoline, and vanillin as described in example 25. This compound was tested against the same cell line of example 25, giving the following results.
Example 27
In this example, 200mg of 4-methyl-6, 7-dihydrothieno [3,2-c ] pyridine of the formula
Reacted with an excess of vanillin by microwave heating the reaction mixture in methanol at 100 ℃ for 30 minutes. Unexpectedly, a spiro solid compound having the formula
It is a MW 588.82 species that hydrogen bonds to a MW 151.14 species. Note that the MW 588.82 substance comprises a single vanillin moiety and three 4-methyl-6, 7-dihydrothieno [3,2-c ] pyridine moieties. This spiro compound (designated HRM 05) was tested against a number of different tissue types by the in vitro cell proliferation assay described above with the following results:
watch 19
TBD = to be determined
Although the anti-cancer properties of the compositions of the invention have been demonstrated to be resistant to certain cancers, it is believed that the invention is applicable to almost all cancers, such as the following: acute lymphocytic leukemia, adult; acute lymphocytic leukemia, childhood; acute myeloid leukemia, adult; acute myeloid leukemia, childhood; adrenocortical carcinoma; adrenocortical carcinoma, childhood; adolescents, cancer; AIDS-related cancers; AIDS-related lymphomas; anal cancer; appendiceal carcinoma; astrocytoma, childhood; atypical teratoma/rhabdoid tumor, childhood, central nervous system; basal cell carcinoma; cholangiocarcinoma, extrahepatic; bladder cancer; bladder cancer, childhood; bone cancer, osteosarcoma and malignant fibrous histiocytoma; brain stem glioma, childhood; brain tumors, adult; brain tumors, brain stem glioma, childhood; brain tumors, central nervous system atypical teratomas/rhabdoid tumors, childhood; brain tumors, central nervous system embryonic tumors, childhood; brain tumors, astrocytomas, childhood; brain tumors, craniopharyngiomas, children; brain tumors, ependymoblastomas, childhood; brain tumor, ependymoma, and childrenA child; brain tumors, medulloblastoma, childhood; brain tumors, myeloepithelioma, childhood; brain tumors, mesogenic pineal parenchyma tumors, childhood; brain Tumors, supratentorial primary neuroectoblastoma (supravital Neuroectodermal Tumors) and pineal blastoma, childhood; brain and spinal cord tumors, childhood (others); breast cancer; breast cancer and pregnancy; breast cancer, children; breast cancer, male; bronchial tumors, childhood; burkitt's (Burkitt) lymphoma; carcinoid tumors, childhood; carcinoid tumors, gastrointestinal tract; primary unknown cancer (Carcinoma of unknown Primary); atypical teratoma/rhabdoid tumor of the central nervous system, childhood; central nervous system embryonic tumors, childhood; central Nervous System (CNS) lymphoma, primary; cervical cancer; cervical cancer, childhood; cancer in children; chordoma, childhood; chronic lymphocytic leukemia; chronic myelogenous leukemia; chronic myeloproliferative disorders; colon cancer; colorectal cancer, childhood; craniopharyngioma, childhood; cutaneous T cell lymphoma; embryonal tumors, central nervous system, childhood; endometrial cancer; ependymoblastoma, childhood; ependymoma, children; esophageal cancer; esophageal cancer, childhood; olfactory neuroblastoma (escherichia), childhood; ewing sarcoma tumor family; extracranial germ cell tumors, children; gonadal ectogenital cell tumors; extrahepatic bile duct cancer; eye cancer, intraocular melanoma; eye cancer, retinoblastoma; gallbladder cancer; gastric (stomach) cancer; gastric (stomach) cancer, childhood; gastrointestinal carcinoid tumors; gastrointestinal stromal tumors (GIST); gastrointestinal stromal cell tumor, childhood; germ cell tumors, extracranial, pediatric; germ cell tumor, extragonadal; germ cell tumors, ovaries; gestational trophoblastic tumors; glioma, adult; glioma, childhood brainstem; hairy cell leukemia; head and neck cancer; heart cancer, childhood; hepatocellular (liver) carcinoma, adult (primary); hepatocellular (liver) cancer, childhood (primary); histiocytosis, langerhans cells; hodgkin lymphoma, adult; hodgkin lymphoma, childhood; hypopharyngeal carcinoma; intraocular melanoma; islet cell tumor (endocrine pancreas); kaposi Sarcoma (Kaposi Sarcoma); renal (renal cell) cancer; kidney cancer, childhood; langerhans cell histiocytosis; laryngeal cancer; laryngeal cancer, childhood; white colour (Bai)Leukemia, acute lymphoblasts, adult; leukemia, acute lymphoblastic cell, childhood; leukemia, acute bone marrow, adult; leukemia, acute bone marrow, childhood; leukemia, chronic lymphocytes; leukemia, chronic myelocytic; leukemia, hair cells; lip and oral cancer; liver cancer, adult (primary); liver cancer, childhood (primary); lung cancer, non-small cell; lung cancer, small cell; lymphoma, AIDS-related; lymphoma, burkitt; lymphoma, cutaneous T cells; lymphoma, hodgkin, adult; lymphoma, hodgkin, childhood; lymphoma, non-hodgkin, adult; lymphoma, non-hodgkin, childhood; lymphoma, primary Central Nervous System (CNS); macroglobulinemia, waldenstromMalignant fibrous histiocytoma of bone and osteosarcoma; medulloblastoma, childhood; medullary epithelioma, childhood; melanoma; melanoma, intraocular (ocular); merkel cell Carcinoma (MerkelCell Carcinoma); mesothelioma, adult malignancy; mesothelioma, childhood; metastatic squamous neck cancer with recessive primary; oral cancer; multiple endocrine tumor syndrome, childhood; multiple myeloma/plasmacytoma; mycosis fungoides; myelodysplastic syndrome; myelodysplastic/myeloproliferative neoplasm; myeloid leukemia, chronic; myeloid leukemia, adult acute; myeloid leukemia, childhood acute; myeloma, polytropy; myeloproliferative disorders, chronic; nasal and paranasal sinus cancer; nasopharyngeal carcinoma; nasopharyngeal carcinoma, childhood; neuroblastoma; non-hodgkin lymphoma, adult; non-hodgkin lymphoma, childhood; non-small cell lung cancer; oral cancer, childhood; oral and lip cancer; oropharyngeal cancer; osteosarcoma and malignant fibrous histiocytoma of bone; ovarian cancer, childhood; epithelial carcinoma of the ovary; ovarian germ cell tumor; ovarian low malignant potential tumors; pancreatic cancer; pancreatic cancer, childhood; pancreatic cancer, islet cell tumor of pancreas; papillomatosis, childhood; paranasal sinus and nasal cavity cancer; parathyroid cancer; penile cancer; pharyngeal cancer; mesogenic pineal parenchymal tumors, children; pineal blastoma and supratentorial primary neuroectoblastoma, childhood; pituitary tumors; seroma-Multiple myeloma; pleuropulmonary blastoma, childhood; pregnancy and breast cancer; primary Central Nervous System (CNS) lymphoma; prostate cancer; rectal cancer; renal cell (renal) carcinoma; renal pelvis and ureter, transitional cell carcinoma; respiratory cancer with altered chromosome 15; retinoblastoma; rhabdomyosarcoma, childhood; salivary gland cancer; salivary gland cancer, childhood; sarcoma, ewing sarcoma family of tumors; kaposi's sarcoma; sarcoma, soft tissue, adult; sarcoma, soft tissue, childhood; sarcoma, uterus; sezary syndrome; skin cancer (non-melanoma); skin cancer, childhood; skin cancer (melanoma); skin cancer, merkel cells; small cell lung cancer; small bowel cancer; soft tissue sarcoma, adult; soft tissue sarcoma, childhood; squamous cell carcinoma; squamous neck cancer with recessive primary, metastatic; gastric (stomach) cancer; gastric (stomach) cancer, childhood; supratentorial primitive neuroectoblastoma, childhood; t cell lymphoma, skin; testicular cancer; testicular cancer, childhood; laryngeal cancer; thymoma and thymus carcinoma; thymoma and thymus carcinoma, childhood; thyroid cancer; thyroid cancer, childhood; transitional cell carcinoma of the renal pelvis and ureter; trophoblastic tumors, pregnancy; unknown primary site, cancer, adult; unknown primary site, cancer, children; rare childhood cancers; ureters and renal pelvis, transitional cell carcinoma; cancer of the urinary tract; uterine cancer, endometrium; uterine sarcoma; vaginal cancer; vaginal cancer, childhood; vulvar cancer; waldenstrom's macroglobulinemia; wilms' tumor; cancer in women. />
Claims (56)
1. An anti-cancer composition comprising a therapeutic compound having a pair of fused tricyclic moieties joined together by a single linker moiety, wherein at least one ring in each fused tricyclic moiety is an N-containing ring, the linker moiety providing a linking branch from a single non-metallic atom forming at least a portion of the linker moiety such that the fused tricyclic moiety is bonded to the linker through the single atom, the linker comprising a methine group, the single non-metallic atom being a carbon atom of the methine group.
2. The composition of claim 1, comprising additional ingredients selected from the group consisting of: active agents, preservatives, buffers, salts, carriers, excipients, diluents and other pharmaceutically acceptable ingredients and combinations thereof.
3. The composition of claim 1, wherein the at least one N-containing ring of each fused tricyclic moiety is a terminal ring thereof.
4. The composition of claim 3, the linking branch being bonded to the terminal N-containing ring of the fused tricyclic moiety.
5. The composition of claim 3, the terminal ring of each fused tricyclic moiety is a six-membered ring.
6. The composition of claim 3, said linking branch being bonded to a carbon atom at an alpha position adjacent to an N atom of said N-containing ring of said fused tricyclic moiety.
7. The composition of claim 1, the linker moiety is derived from an aldehyde compound.
8. The composition of claim 7, the linker is an aldehyde moiety selected from the group consisting of: vanillin, benzaldehyde, cinnamaldehyde, cuminaldehyde, o-vanillin, vanillin isobutyrate, phenoxybenzaldehyde, and mixtures thereof.
9. The composition of claim 7, wherein the linker moiety is derived from a compound having the structure
Wherein the substituents may be located at any position around the ring, R1' is a C1-C12 aldehyde, and R2' -R5' is independently and optionally selected from the group consisting of: H. OH, a C1-C12 alkyl group, a C2-C12 alkenyl group, a C1-C12 alkoxy group, a C1-C12 aldehyde group, an acetate group, an isobutyrate group, a phenyl group, a phenoxy group, a benzyloxy group, a C2-C6 alkyl ester, a halogen and a nitro group, wherein the dotted bond line in the six-membered ring indicates that the six-membered ring may be cyclohexane or have one, two or three carbon-carbon double bonds, or a C1-C12 alkyl or C2-C12 alkenyl aldehyde, said single atom being the carbonyl carbon of said aldehyde group.
10. The composition of claim 1, the tricyclic moieties each being a beta-carboline moiety, wherein each beta-carboline moiety is independently selected from and derived from a compound having the structure
Wherein the numbered 6 membered fused ring is an N-heterocycle having a single N atom at any of the 2-5 positions, and the R6 substituent may be at any ring position, R5 'is H or C1-C12 alkoxy, and R6' is H, C1-C12 alkyl or C1-C12 carboxylic acid.
11. The composition of claim 1, in a form selected from the group consisting of: liquid dispersions, capsules, pills, tablets, and combinations of any of the foregoing.
12. The composition of claim 1, the therapeutic compound having two hamalin moieties and a single linker moiety derived from an aldehyde compound.
13. The composition of claim 12, the aldehyde moiety selected from the group consisting of: vanillin, benzaldehyde, cinnamaldehyde, cuminaldehyde, o-vanillin, vanillin isobutyrate, phenoxybenzaldehyde, and mixtures thereof.
14. The composition of claim 1, the therapeutic compound having two hamalin moieties and a cinnamaldehyde moiety, and having a molecular weight of about 542.
15. The composition of claim 1, the therapeutic compound having the structure
Wherein the-O-R3 group can be independently located at any position on the terminal phenyl group, wherein each R1 is independently selected from the group consisting of: H. OH and C1-C12 alkyl groups, each R2 is independently selected from the group consisting of: H. OH and C1-C12 alkyl groups, each R3 group is independently selected from the group consisting of: a C1-C12 alkyl group and a substituted or unsubstituted phenyl group, and wherein the symbolsRefers to the fact that the following may optionally be present: 1) One or two non-fused double bonds located at one or two valency-allowed positions around either or both six-membered N-containing rings; 2) Double bonds between either or both of the N-containing rings and adjacent carbons of the central moiety, with or without additional non-fused double bonds at any valency-allowed position around the corresponding N-containing ring; or 3) either or both of the N-containing rings do not contain non-fused double bonds, and each R1 is independently selected from the group consisting of: H. OH and C1-C12 alkyl groups.
17. The composition of claim 1, wherein the therapeutic compound comprises two hamalin moieties and one vanillin moiety.
18. The composition of claim 1, the therapeutic compound having the structure
Wherein each R4 is independently selected from the group consisting of: absent, H, OH and C1-C12 alkyl groups, each R5 is independently selected from the group consisting of: H. OH and C1-C12 alkyl groups, each R6 group being independently located at any position around the respective terminal phenyl group, or at either of the two open positions of the two N-containing rings, and being selected from the group consisting of: a C1-C12 alkoxy group, H, OH, and a substituted or unsubstituted phenyl group, R7 and R8 are attached at any position around the phenyl ring and are independently selected from the group consisting of: H. OH and C1-C12 alkoxy groups, with the proviso that R7 and R8 are not both H, R7 is OH, R8 is a C1-C12 alkoxy group, and each R9 is independently selected from the group consisting of: H. OH and C1-C12 alkyl groups, and wherein the labelRefers to the fact that the following may optionally be present: 1) Zero, one, or two non-fused double bonds, located at one or two valency-allowed positions around either or both six-membered N-containing rings; 2) A double bond between either or both of the N-containing rings and the adjacent carbon of the central moiety, with or without an additional non-fused double bond, at any valency-allowed position around the corresponding N-containing ring, provided that in the case of 2) where there is a double bond between a nitrogen atom of either N-containing ring and its adjacent carbon atom, R4 is absent, provided that if there is no such nitrogen double bond, the corresponding R4 is selected from the group consisting of: H. OH and C1-C12 alkyl groups; or 3) either or both of the N-containing rings do not contain non-fused double bonds, and each R4 is independently selected from the group consisting ofGroup (2): H. OH and C1-C12 alkyl groups.
21. The composition of claim 1, the therapeutic compound having the structure
Wherein the-O-R3 group can be independently located at any position on the terminal phenyl group, wherein each R1 is independently selected from the group consisting of: absent, H, OH and C1-C12 alkyl groups, each R2 is independently selected from the group consisting of: H. OH and C1-C12 alkyl groups, each R3 group is independently selected from the group consisting of: a C1-C12 alkyl group and a substituted or unsubstituted phenyl group, and wherein the symbolsRefers to the fact that the following may optionally be present: 1) One or two non-fused double bonds located at one or two valency-allowed positions around either or both six-membered N-containing rings; 2) Double bonds between either or both of the N-containing rings and adjacent carbons of the central moiety, with or without additional non-fused double bonds at any valency-allowed position around the corresponding N-containing ring;or 3) either or both of the N-containing rings do not contain non-fused double bonds, and each R1 is independently selected from the group consisting of: H. OH and C1-C12 alkyl groups.
23. The composition of claim 1, the therapeutic compound having the structure
Wherein the-O-R3 group can be independently located at any position on the terminal phenyl group, wherein each R1 is independently selected from the group consisting of: absent, H, OH and C1-C12 alkyl groups, each R2 is independently selected from the group consisting of: H. OH and C1-C12 alkyl groups, each R3 group is independently selected from the group consisting of: a C1-C12 alkyl group and a substituted or unsubstituted phenyl group, and the phenoxy group may be substituted at any position on the benzyl ring, and wherein the labelRefers to the fact that the following may optionally be present: 1) One or two non-fused double bonds located at one or two valency-allowed positions around either or both six-membered N-containing rings; 2) Double bonds between either or both of the N-containing rings and adjacent carbons of the central moiety, with or without additional non-fused double bonds at any valency-allowed position around the corresponding N-containing ring; or 3) either or both of the N-containing rings do not contain non-fused double bonds, and each R1 is independently selected from the group consisting of: H. OH and C1-C12 alkyl groups.
25. The composition of claim 1, the therapeutic compound having the structure
Wherein each of X1, X2 and X3 is independently selected from the group consisting of: -absent, H, OH, C1-C12 alkyl, alkenyl and alkynyl groups, C1-C12 alkoxy and alkoxyphenyl groups, aryl and aryloxy groups, aldehyde and formaldehyde groups, amines, nitro groups, nitrile groups, C2-C6 carboxylic acid groups, boronic acid groups, sulfur groups and amino acids, wherein any of the above mentioned may be substituted by N, S, O, B or halogen atoms, Z is a carbon atom of the methine group, X9 is OH, C1-C12 alkyl, alkenyl and alkynyl groups, C1-C12 alkoxy and alkoxyphenyl groups, aryl and aryloxy groups, aldehyde and formaldehyde groups, amines, nitro groups, nitrile groups, C2-C6 carboxylic acid groups, boronic acid groups, sulfur groups and amino acids, wherein any of the above-mentioned may be substituted with an N, S, O, B, or halogen atom, each X3 is attached at any position around the corresponding terminal phenyl moiety of the beta-carboline group, each Y is independently absent, a C1-C12 alkyl, alkenyl, and alkynyl group, a C1-C12 alkoxy and alkoxyphenyl group, an aryl and aryloxy group, an aldehyde group, an amine, a nitro group, a nitrile group, a C2-C6 carboxylic acid group, a boronic acid group, a sulfur group, and an amino acid, wherein any of the above-mentioned may be taken by an N, S, O, B, or halogen atomAnd, Y is a C1-C12 group consisting of C, CH and/or CH2 atoms or groups, M is selected from the group consisting of: structure IIIA, absent, OH, C1-C12 alkyl, alkenyl and alkynyl groups, C1-C12 alkoxy and alkoxyphenyl groups, aryl and aryloxy groups, aldehyde groups, amines, nitro groups, nitrile groups, C2-C6 carboxylic acid groups, boronic acid groups, sulfur groups and amino acids, wherein any of the above mentioned may be substituted with N, S, O, B or halogen atoms, each of X4, X5, X6, X7 and X8 in structure IIIA is attached at any position around the a ring and is independently selected from the group consisting of: absent, H, OH, C1-C12 alkyl, alkenyl and alkynyl groups, C1-C12 alkoxy and alkoxyphenyl groups, aryl and aryloxy groups, aldehyde groups, amines, nitro groups, nitrile groups, C2-C6 carboxylic acid groups, boronic acid groups, sulfur groups and amino acids, any of which mentioned above may be substituted by N, S, O, B or halogen atoms, the label in the A ringRefers to the fact that 0, 1,2 or 3 double bonds may optionally be present and in which a marker attached to both B rings->Means that may optionally be present
The following facts: 1) One or two non-fused double bonds located at one or two valency allowed positions around either or both of the B rings; 2) The double bond between either or both of the B rings and Y or Z, with or without additional non-fused double bonds at any valency-permitting position around the corresponding N-containing ring.
26. The composition of claim 25, wherein M is a 1A ring, both X1 are absent, both X3 are methoxy, 2 of X4, X5, X6, X7, and X8 are H, at least one of X4, X5, X6, X7, and X8 is selected from the group consisting of: H. -OH, methoxy, ethoxy, phenoxy, C2-C5 alkenyl groups, F and Cl with the proviso that: 1) When one or more of X4, X5, X6, X7 and X8 is F or Cl, the remainder of X4, X5, X6, X7 and X8 is H; 2) Only one of X4, X5, X6, X7 and X8 may be phenoxy, and in such a case, the remainder of X4, X5, X6, X7 and X8 is H.
28. an anti-cancer composition comprising a therapeutic compound that is a reaction product of an aldehyde compound and hamamelin, the reaction product comprising two hamamelin moieties covalently bonded to a single linker moiety derived from the aldehyde compound, the composition comprising at least one other ingredient in addition to the reaction product.
29. The composition of claim 28, the aldehyde compound selected from the group consisting of: vanillin, cinnamaldehyde, o-vanillin, phenoxybenzaldehyde, and mixtures thereof.
30. The composition of claim 28, the therapeutic compound having the general structure II:
wherein X10 is-CH = CH-, X11, X12, X13 and X14 are each independently selected from the group consisting of: H. -OH, methoxy, ethoxy and phenoxy, F and Cl, with the proviso that: 1) At least one of X12, X13 or X14 is H; 2) When one or more of X11, X12, X13 or X14 is F or Cl, the remainder of X11, X12, X13 and X14 is H; 3) Phenoxy groups are present only at X12 and X11, X13 and X14 are all H, and 4) if methoxy or ethoxy groups are present, at least one such methoxy or ethoxy group must be located at the 2 or 3 position, wherein the label attached to the two N-containing rings — refers to the fact that the following may optionally be present: 1) One or two non-fused double bonds located at one or two valency-allowed positions around either or both of the N-containing rings; 2) Double bonds between either or both of the N-containing rings and adjacent carbon atoms, with or without additional non-fused double bonds at any valency-allowed position around the corresponding N-containing ring; or 3) either or both of the N-containing rings do not contain non-fused double bonds, and each X1 is independently selected from the group consisting of: H. OH and C1-C12 alkyl groups.
31. A compound having a pair of fused tricyclic moieties joined together by a single linker moiety, wherein one ring in each fused tricyclic moiety is an N-containing ring, said linker moiety providing a linking branch from a single non-metallic atom forming at least a part of said linker moiety such that said fused tricyclic moiety is bonded to said linker through said single atom, said linker comprising a methine group, said single non-metallic atom being a carbon atom of said methine group, with the proviso that said compound does not have two hamameline moieties or two harmine moieties with a linker moiety of benzaldehyde or p-nitrobenzaldehyde.
32. The compound of claim 31, the linker moiety is derived from an aldehyde compound.
33. The compound of claim 32, the linker moiety is derived from a compound having the structure
Wherein the substituents may be located anywhere around the ring, R1' is a C1-C12 aldehyde, and R2' -R5' are independently and optionally selected from the group consisting of: H. OH, a C1-C12 alkyl group, a C2-C12 alkenyl group, a C1-C12 alkoxy group, a C1-C12 aldehyde group, an acetate group, an isobutyrate group, a phenyl group, a phenoxy group, a benzyloxy group, a C2-C6 alkyl ester, a halogen and a nitro group, wherein the dotted bond line in the six-membered ring indicates that the six-membered ring may be cyclohexane or have one, two or three carbon-carbon double bonds, or a C1-C12 alkyl or C2-C12 alkenyl aldehyde, said single atom being the carbonyl carbon of said aldehyde group.
34. The compound of claim 31, the tricyclic moieties each being a β -carboline moiety, wherein each β -carboline moiety is independently selected from and derived from a compound having the structure
Wherein the numbered 6-membered fused ring is an N-heterocycle having a single N atom at any of positions 2-5, and the R6 substituent may be at any ring position, R5 'is H or C1-C12 alkoxy, and R6' is H, C1-C12 alkyl, or C1-C12 carboxylic acid.
35. The compound of claim 31, the linker is an aldehyde moiety selected from the group consisting of: vanillin, benzaldehyde, cinnamaldehyde, cuminaldehyde, o-vanillin, vanillin isobutyrate, phenoxybenzaldehyde, and mixtures thereof.
36. A compound according to claim 31, having two hamalin moieties and a single linker moiety derived from an aldehyde compound.
37. The compound of claim 36, the aldehyde moiety selected from the group consisting of: vanillin, benzaldehyde, cinnamaldehyde, cuminaldehyde, o-vanillin, vanillin isobutyrate, phenoxybenzaldehyde, and mixtures thereof.
38. The compound of claim 31, having two hamamelin moieties and a cinnamaldehyde moiety, and having a molecular weight of about 542.
39. The compound of claim 31, having the structure
And dimers, isomers, and tautomers thereof, wherein the-O-R3 group can be independently located at any position on the terminal phenyl group, wherein each R1 is independently selected from the group consisting of: absent, H, OH and C1-C12 alkyl groups, each R2 is independently selected from the group consisting of: H. OH and C1-C12 alkyl groups, each R3 group being independently selected from the group consisting of: a C1-C12 alkyl group and a substituted or unsubstituted phenyl group, and wherein the symbolsRefers to the fact that the following may optionally be present: 1) One or two non-fused double bonds located at one or two valency-allowed positions around either or both six-membered N-containing rings; 2) Double bonds between either or both of the N-containing rings and adjacent carbons of the central moiety, with or without additional non-fused double bonds at any valency-allowed position around the corresponding N-containing ring; or 3) either or both of the N-containing rings do not contain non-fused double bonds, and each R1 is independently selected from the group consisting of: H. OH and C1-C12 alkyl groups.
41. The compound of claim 31, comprising two hamalin moieties and one vanillin moiety.
42. The compound of claim 31, having the structure
Wherein each R4 is independently selected from the group consisting of: absent, H, OH and C1-C12 alkyl groups, each R5 is independently selected from the group consisting of: H. OH and C1-C12 alkyl groups, each R6 group being independently located at any position around the respective terminal phenyl group, or at either of the two open positions of the two N-containing rings, and being selected from the group consisting of: a C1-C12 alkoxy group, H, OH, and a substituted or unsubstituted phenyl group, R7 and R8 are attached at any position around the phenyl ring and are independently selected from the group consisting of: H. OH and C1-C12 alkoxy groups, with the proviso that R7 and R8 are not both H, R7 is OH, R8 is a C1-C12 alkoxy group, and each R9 is independently selected from the group consisting of: H. OH and C1-C12 alkyl groups, and wherein the symbolsRefers to the fact that the following may optionally be present: 1) Zero, one, or two non-fused double bonds, located at one or two valency-allowed positions around either or both six-membered N-containing rings; 2) Double bonds between either or both of the N-containing rings and the adjacent carbon of the central moiety, with or without additional non-fused double bonds at any valency-allowed position around the corresponding N-containing ring, provided that 2) there is a bond between the nitrogen atom of either of the N-containing rings and its adjacent carbon atomIn the case of a double bond, R4 is absent, provided that if there is no such nitrogen double bond, the corresponding R4 is selected from the group consisting of: H. OH and C1-C12 alkyl groups; or 3) either or both of the N-containing rings do not contain non-fused double bonds, and each R4 is independently selected from the group consisting of: H. OH and C1-C12 alkyl groups.
45. The compound of claim 31, having the structure
Wherein the-O-R3 group can be independently located at any position on the terminal phenyl group, wherein each R1 is independently selected from the group consisting of: (ii) absent, H, OH and C1-C12 alkyl groups, each R2 is independently selected from the group consisting of: H. OH and C1-C12 alkyl groups, each R3 group is independently selected from the group consisting of: a C1-C12 alkyl group and a substituted or unsubstituted phenyl group, and wherein the symbolsRefers to the fact that the following may optionally be present: 1) One or two non-condensed double bonds in a six-membered N-containing ringOne or two valency-allowed positions around either or both; 2) Double bonds between either or both of the N-containing rings and adjacent carbons of the central moiety, with or without additional non-fused double bonds at any valency-allowed position around the corresponding N-containing ring; or 3) either or both of the N-containing rings do not contain non-fused double bonds, and each R1 is independently selected from the group consisting of: H. OH and C1-C12 alkyl groups.
47. The compound of claim 31, having the structure
Wherein the-O-R3 group can be independently located at any position on the terminal phenyl group, wherein each R1 is independently selected from the group consisting of: absent, H, OH and C1-C12 alkyl groups, each R2 is independently selected from the group consisting of: H. OH and C1-C12 alkyl groups, each R3 group being independently selected from the group consisting of: a C1-C12 alkyl group and a substituted or unsubstituted phenyl group, and the phenoxy group may be substituted at any position on the benzyl ring, and wherein the labelRefers to the fact that the following may optionally be present: 1) One or two non-fused double bonds located at one or two valency-allowed positions around either or both of the six-membered N-containing rings; 2) The double bond between either or both of the N-containing rings and the adjacent carbon of the central moiety has at any valency-permitting position around the corresponding N-containing ringOr no additional non-fused double bonds; or 3) either or both of the N-containing rings do not contain non-fused double bonds, and each R1 is independently selected from the group consisting of: H. OH and C1-C12 alkyl groups.
50. a method of treating a human cancer patient comprising the step of administering to said patient an effective amount of the composition of claim 1.
51. A method according to claim 50, the compound comprising two hamalin moieties covalently bonded to a single moiety derived from an aldehyde compound.
52. The method of claim 51, the aldehyde is selected from the group consisting of: vanillin, benzaldehyde, cinnamaldehyde, o-vanillin, phenoxybenzaldehyde, and mixtures thereof.
53. Use of a composition according to any one of claims 1-30 for the manufacture of a medicament for anticancer therapeutic application.
54. A composition for use in the treatment of cancer in a human, said composition being according to any one of claims 1-30.
55. A pharmaceutical composition for treating cancer comprising a therapeutically effective amount of the composition of any one of claims 1-30 and a pharmaceutically acceptable carrier.
56. A pharmaceutical composition for the treatment of cancer comprising administering a therapeutically effective amount of a composition according to any one of claims 1-30, in a pharmaceutically acceptable carrier, prepared by processes known per se.
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US4631323A (en) * | 1985-07-29 | 1986-12-23 | Honeywell Inc. | Method of making conducting polymer complexes of N-substituted carbazoles and substituted benzaldehydes |
AU2001274827A1 (en) * | 2000-05-09 | 2001-11-20 | The Regents Of The University Of California | Porphyrin-based neutron capture agents for cancer therapy |
EP2050747A1 (en) * | 2007-10-12 | 2009-04-22 | BioAlliance Pharma | Dimers of harmol or of its derivatives and uses thereof |
CN101367802B (en) * | 2008-09-27 | 2012-09-05 | 暨南大学 | Beta-kabarin alkaloids in quassia wood, preparation method and application thereof |
US9907786B2 (en) * | 2014-10-21 | 2018-03-06 | Ions Pharmaceutical S.À R.L. | Therapeutic compositions containing harmine and isovanillin components, and methods of use thereof |
US10947253B2 (en) * | 2019-08-05 | 2021-03-16 | Ankh Life Sciences Limited | Fused polycyclic dimers |
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