WO2014084898A1 - Novel synthetic antioxidants and their uses - Google Patents

Novel synthetic antioxidants and their uses Download PDF

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WO2014084898A1
WO2014084898A1 PCT/US2013/037038 US2013037038W WO2014084898A1 WO 2014084898 A1 WO2014084898 A1 WO 2014084898A1 US 2013037038 W US2013037038 W US 2013037038W WO 2014084898 A1 WO2014084898 A1 WO 2014084898A1
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disease
novel
acid
thiol
antioxidants
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PCT/US2013/037038
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French (fr)
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Yansong Lu
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Yansong Lu
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Priority to US14/647,260 priority Critical patent/US9994519B2/en
Priority to CN201380062091.5A priority patent/CN104812736A/en
Priority to EP13859245.6A priority patent/EP2925719A4/en
Publication of WO2014084898A1 publication Critical patent/WO2014084898A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C327/00—Thiocarboxylic acids
    • C07C327/02—Monothiocarboxylic acids
    • C07C327/04—Monothiocarboxylic acids having carbon atoms of thiocarboxyl groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C327/06—Monothiocarboxylic acids having carbon atoms of thiocarboxyl groups bound to hydrogen atoms or to acyclic carbon atoms to hydrogen atoms or to carbon atoms of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C321/00—Thiols, sulfides, hydropolysulfides or polysulfides
    • C07C321/24—Thiols, sulfides, hydropolysulfides, or polysulfides having thio groups bound to carbon atoms of six-membered aromatic rings
    • C07C321/26—Thiols
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C327/00—Thiocarboxylic acids
    • C07C327/18—Dithiocarboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C327/00—Thiocarboxylic acids
    • C07C327/20—Esters of monothiocarboxylic acids
    • C07C327/26—Esters of monothiocarboxylic acids having carbon atoms of esterified thiocarboxyl groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C327/00—Thiocarboxylic acids
    • C07C327/38—Amides of thiocarboxylic acids
    • C07C327/48—Amides of thiocarboxylic acids having carbon atoms of thiocarboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/65—One oxygen atom attached in position 3 or 5
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/83—Thioacids; Thioesters; Thioamides; Thioimides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/38—One sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • This invention relates to novel synthetic organic antioxidants of small molecules, their rational design, their proposed chemical preparation, and their potential uses in application to treatment and/or prevention of major diseases associated with oxidative stress.
  • any harmful oxidants are efficiently neutralized by corresponding reductases in a timely manner so as to protect important biological m acrom o I ec u 1 es such as proteins, DNA and lipids, from being oxidized.
  • important biological maCromolecules such as proteins, DNA and lipids
  • ROS reactive oxygen species
  • RNS reactive nitrogen species
  • Free radicals from internal source are actually generated from normal metabolic cycles. Part of them is used by immune system to light against the invasion of bacteria or virus. Their functions also include redox signaling, cleaning up death cells, activating and modulating some important life processes, etc. Overall, free radicals from internal source are often kept under control by the redox system.
  • External source includes cigarette smoke, alcoholism, toxins, certain drugs, ozone, UV light, radiation, pesticides, herbicides, environmental pollutants, etc.
  • the third source is related to physiological factors, including stress, emotion, disease conditions, etc. Free radicals from the latter two sources are usually extra burdens of the redox system and they are the roots of oxidative stress that causes health problems.
  • Free radicals have been implicated in the etiology of large number of major diseases, such as Alzheimer's disease, Parkinson's disease, cancers, diabetes, HIV, acne, cardiovascular disease, renal disease, hypertension, hypercholesterolemia, hyperlipidemia, rheumatoid arthritis, inflammation, pain, aging, stroke, cataract, glaucoma, age-related macular degeneration, etc.
  • Antioxidants that can combat free radicals have drawn significant attention in past decades. Natural sources of antioxidants include fruits, vegetables and other dietary.
  • Herbal polyphenols, flavonoids, beta-carotene, vitamin A, vitamin C, vitamin E, lipoic acid, dithiolethione, ovothiol, glutathione and melatonin are some examples of naturally occurring antioxidants.
  • some problems might be encountered when naturally occurring antioxidants are directly used as drugs. Their bioavailability may not be good enough because many of them have poor solubility in water. Their antioxidant power may not precisely fit in the indication.
  • Some polyphenols can form precipitates with proteins (enzymes) down the digestive tract, resulting in poor bioavailability and causing digestion issue.
  • Oltipraz, DTT (dithiothreitol), probucol and succinobucol are other examples of synthetic organic antioxidants. None of these has been approved as antioxidant drug, although oltipraz is used as a schistosomicide. But the advantages of synthetic organic antioxidants arc clear that they can be designed in such a way to enhance the bioavailability, to minimize their toxicities, to tunc in the scavenging power on free radicals, and so forth. Synthetic antioxidants can certaihly play an important role in treatment and/or prevention of major diseases thai are associated with oxidative stress.
  • antioxidants are a class of compounds that can deactivate reactive oxidants by fnians of being oxidized themselves.
  • the organic antioxidants are often aniline-like compounds (including ifdole-like), phenol or polyphenol compounds, thiol-containing compounds and selenol-containing compounds.
  • both reduced form and oxidized form of the ideal antioxidant should not have any toxicity issues.
  • phosphine compounds are known to be easily oxidized and can be good antioxidants in chemical wise. But they are ruled out as drugs due to toxicity issues.
  • a drug-to-be molecule of organic antioxidant should first be a nitrogen-containing, oxygen-containing, sulfur-containing, or selenium-
  • An interesting example of synthetic phenolic antioxidant is succinobucol (AGI- 1067) of AtheroGenics, which is similar to BHT in structure as shown in Figure III.
  • Cysteine is a sulfur-containing, naturally occurring amino acid, well known for its function in biological redox system. Its oxidized form, cystine, plays an important role in
  • antioxidants such as vitamin A, vitamin C, vitamin E, melatonin, beta-carotene
  • diseases such as neurodegenerative diseases, cancer, inflammation, atherosclerosis, aging, etc.
  • No efficacy, marginal benefits or controversial results have been obtained.
  • vitamin A, vitamin E, and beta-carotene even leads to higher adverse effects, such as higher mortality or higher risk of certain cancers.
  • This invention is directed to novel dithiol-containing compounds which possess strongest possible capability as both scavenger for free radicals and antioxidant, their rational design, their proposed preparations by means of synthetic organic chemistry, and their potential uses in application to treatment and or prevention of major diseases associated with oxidative stress, such as Alzheimer's disease, Parkinson's disease, cancer, diabetes, HIV, acne, cardiovascular disease, renal disease, hypertension, hyperlipidemia, h y perc ho 1 est era 1 em i a . rheumatoid arthritis, inflammation, pain, aging, stroke, cataract, glaucoma, age-related macular degeneration, etc.
  • major diseases associated with oxidative stress such as Alzheimer's disease, Parkinson's disease, cancer, diabetes, HIV, acne, cardiovascular disease, renal disease, hypertension, hyperlipidemia, h y perc ho 1 est era 1 em i a .
  • rheumatoid arthritis inflammation, pain, aging, stroke, cataract, glaucoma, age-
  • a compound In order to be used as an antioxidant, a compound must consist of at least one functional group that can be readily oxidized. From the periodic table of the elements, the functional group of a drug-to-be organic antioxidant must consist of at least an atom of low valent nitrogen, oxygen, sulfur, or selenium.
  • the order of antioxidant strength is selenophenol>thiophenol>aniline>phenol, based on chemistry theory.
  • the order of antioxidant strength is thiophenol>alkyl thiol; aniline>alkyl amine, and so forth.
  • the strength of a free radical scavenger is not identical to its strength as an
  • Antioxidant drugs should: etter be in their "reduced forms". When quenching frees radicals, they are oxidized and become “oxidized forms”. The “oxidized forms” are not active and have no more capability of quenching free radicals.
  • Thiol and thiophenol are the “reduced forms" of antioxidant drugs, but are unstable for storage because they are prone to air oxidation. Hence, thiol and thiophenol must be chemically protected by other functional groups in order for a drug to be stored under atmosphere. At this point, the protected one is a pro ⁇ 3 ⁇ 4g : that can release the drug as active "reduced form " in vivo where the protection group is chemically disconnected.
  • the protection groups selected in this invention alsp adli as penetration enhancer in order for a drug to be better delivered. In addition, the protection groups must have no toxicity issue.
  • each novel molecule in this invention consists of at least two thiol groups.
  • the sterical configuration allow s them to fonn a 5 or 6-membered ring with a new disulfide bond in the ring.
  • the thiol group is covalently single-bonded with a carbon atom located on aromatic ring, at benzyl ie position of aromatic ring, or at allylic position.
  • thiophenol is stronger antioxidant than alkyl thiol.
  • A-L basic categories
  • variable part is the matrix that can be either regular aromatic ring or aromatic heterocyclic ring, with any possible combinations. Therefore, a large variety of new compounds are designed, with consideration of drug delivery that usually requires drug compounds to be amph i pat h i c .
  • the novel, drug-to-be molecules are numbered in Arabic hereafter unless otherwise notified.
  • Aspirin is probably the most popular drug in history. It is widely used in many indications as pain-killer, anti-inflammation, fever-reducer, preventing stroke and heart attack, etc. Expanded applications of aspirin in treatment and/or prevention of Alzheimer's disease, cancer and diabetes are under wide studies in recent years.
  • Compound 1 is the mimic of aspirin ( Figure 2 of drawings), as a drug candidate in this invention.
  • Compound la the mimic of salicylic acid, would he the active form of compound 1 in vivo.
  • lc is a known compound, compound lb w ould reasonably be the oxidized form of compound la.
  • Vitamin E is a naturally occurring antioxidant and served as an important dietary nutrition.
  • Vitamin E family has two groups: tocopherols and tocotrienols. Each group has four forms: alpha (a), beta ( ⁇ ), gamma ( ⁇ ), an Selta ( ⁇ ).
  • the capability of vitamin E as antioxidant and free radical scavenger is ihferi6r to that of novel drug molecules in this invention. Besides, its bioavailability if poor due to low solubility in water.
  • Some novel designs of vitamin E mimics arc depicted ( Figure 5 of drawings). There are more novel molecules of vitamin li mimics with extended structure alteration ( Figure 6 of draw ings).
  • 1.8-I)ithionaphthalene represents a class of most powerful scavengers for free radicals in this invention, as both thiols are thiophenol-like and it forms a 5-mcmbcrcd ring when oxidized. Novel drug molecules on skeleton of 1.8-dithionaphthaleno with di ITerent protection i sjiips are depicted ( Figure 7 of drawings).
  • Vitamin B6 pyridoxine
  • vitamin B3 niacin
  • Figure 8 of drawings Some novel designs of their mimics with different protection groups are depicted ( Figure 8 of drawings). They are similar to those molecules in Figure 3 and Figure 4 of drawings. Instead of benzene matrix, these are on pyridine matrix. Some novel molecules on pyrimidine or pyrazine matrix are also depicted ( Figure 9 of drawings).
  • Folic acid (vitamin B9) is an important nutrition for embryo development.
  • cancer cells need high amount o folic acid for high grow th rate. This may shed light for folic acid mimics to selectively deliver drug to cancer cells.
  • Some novel molecules of folic acid mimics arc depicted ( Figure 10 of drawings).
  • Melatonin is a hormone secreted by the pineal gland in the brain. It helps regulate sleep-wake cycle. It is also served as antioxidant according to some publications. Some novel molecules of melatonin mimics are depicted ( Figure 11 of draw ings).
  • Riboflavin (vitamin B2) is a water-soluble vitamin and is required for many cellular processes. Some novel molecules of its mimics are depicted ( Figure 12 of drawings). The heterocyclic part of riboflavin is retained for the sake of drug delivery. For each of basic styles in figure 1 of drawings, numerous molecules can be drawn. For a flavor of that, several novel compounds are depicted ( Figure 13 and Figure 14 of drawings). The mimics of some naturally occurring products outlined above can certainly play a key role in this invention. Molecular structure optimization of the numbered compounds can be made based on the data feedback from their pre-clinical tests, such as efficacy, ADME, DMPK, etc. Good drug candidates will be moved forward to clinical trial and beyond.
  • Free radical oxidation has been reported to associate with following indications, Alzheimer's disease, Parkinson's disease, diabetes, cardiovascular disease, cancer, renal disease, hypertension, hypercholesterolemia, hyperlipidcmia, rheumatoid arthritis, pain, inflammation, stroke, HIV, aging, acne, cataract, age-related macular degeneration, glaucoma, etc.
  • novel: drug molecules in this invention could be applied to treatment and/or prevent ion of these indications.
  • Age-related cataract is cloudiness of lens that consists of proteins and water.
  • the proteins in lens are transparent in normal array. When oxidized by free radicals, the lens proteins become cross-linked by forming disulfide bonds, leading to structure change of the proteins and distortion of protein array in lens, and resulting in permanent cloudiness.
  • Surgical removal opaque lens and implanting artificial lens is the only therapy for cataract patients. Surgery therapy is simple, but relatively costly.
  • novel drug molecules in this invention as the highest powerful scavengers of free radicals could have highly promising therapeutic effects in both treatment and prevention of age-related cataract.
  • the cornea barrier is a challenger for drug delivery of eye drop medication. This issue would be addressed by several novel drug molecules in this invention designed as amphipathic compounds.
  • Alzheimer's disease is caused by Sclerosis of beta-amyloid (peptide) and/or fibrosis of tau protein in the brain. Free radical oxidation is a prime suspect for these protein tangles. There is currently no therapy for Alzheimer ' s disease. Therefore, there is an urgently need to have a drug to prevent this disease, to stop the progress of this disease, or even to cure this disease.
  • beta-amyloid peptide
  • novel drug molecules in this invention possessing the highest pow erful scavengers of free radicals could have promising therapeutic effects in both treatment and prevention of Alzheimer's disease.
  • Blood-brain barrier is a challenger for drug delivery of brain medication. This issue would be addressed by several novel drug molecules in this invention designed with moiety of choline, dopamine, amino acids, etc. Similar applications could be for Parkinson's disease and other neurodegenerative diseases associated with oxidative stress.
  • LDL Low density lipoprotein
  • the oxidized LDL can become plaques and hard to remove, leading to narrower blood vessel, causing ischemic stroke and cardiovascular diseases.
  • the oxidized lipids are the suspected causes of inflammation.
  • the novel drug molecules in this invention possessing the highest powerful scavengers of free radicals would find applications in prevention and/or treatment of rheumatoid arthritis, ischemic stroke and relevant cardiovascular diseases, such as atherosclerosis, hyperlipidemia, heart attack, etc.
  • Oxidative stress has been associated ith many cancers.
  • Some novel antioxidant molecules in this invention, especially novel molecules of folic acid mimics, would find applications in prevention and/or treatment of cancers, such as liver cancer, lung cancer, pancreatic cancer, stomach cancer, breast cancer, prostate cancer, colon cancer, etc.
  • Typical synthetic routes of novel compounds 1 and 74 in this invention have been show n in sctifeiie 2 of drawings.
  • Starting material thiophenol is commercially available, which can also be synthesized from bromobenzene via Grignard reaction as reported. Lithiation of thiophenol gives ortho-directed lithiation intermediate. The lithiated intermediate reacts with carbon disulfide, followed by acctylation to afford compound 1.
  • Pyridoxine (vitamin B6) treated with thionyl chloride could give di-chloride intermediate as shown in scheme 2 of drawings. The di-chloride intermediate could efficiently react with compound 1 to afford compound 74 in the presence of sodium bicarbonate and phase transfer catalyst (PTC) such as tetrabuty lam mon i um bromide (TBAB).
  • PTC phase transfer catalyst

Abstract

The present invention relates to synthetic organic antioxidants of small molecules. The novel dithiol-containing compounds in this invention possess strongest possible capability as both scavenger for free radicals and antioxidant. This invention is directed to novel molecules as prodrugs of the novel dithiol-containing compounds, their rational design, their feasible preparation route by means of synthetic organic chemistry, and their potential uses in application to treatment and/or prevention of major diseases associated with oxidative stress, such as Alzheimer's disease, Parkinson's disease, cancer, diabetes, HIV, acne, cardiovascular disease, renal disease, hypertension, hypercholesterolemia, hyperlipidemia, rheumatoid arthritis, inflammation, pain, aging, stroke, cataract, glaucoma, age-related macular degeneration, etc.

Description

NOVEL SYNTHETIC ANTIOXIDANTS AND THEIR USES
(Inventor: Yansong Lu; Date: 4-15-2013; email: yansonglu(¾faotmail .com)
The present application claims benefit of priority to U.S. Provisional Application Serial No. 61/730,508 filed on November 28, 2012, the entire contents of which are herein incorporated by reference.
FIELD OF THE INVENTION
This invention relates to novel synthetic organic antioxidants of small molecules, their rational design, their proposed chemical preparation, and their potential uses in application to treatment and/or prevention of major diseases associated with oxidative stress.
BACKGROUND OF THE INVENTION
There is a delicate-regulated redox system in living organism. In a healthy human body, any harmful oxidants, whether from endogenous or exogenous origin, are efficiently neutralized by corresponding reductases in a timely manner so as to protect important biological m acrom o I ec u 1 es such as proteins, DNA and lipids, from being oxidized. However, under unbalanced conditions when there are more amounts of harmful oxidants than the capacity of reductases to deal with, which is called the state of oxidative stress, excessive oxidants can oxidize important biological maCromolecules such as proteins, DNA and lipids, leading to malfunction or dysfunction of these important biological macromolecules and resulting in serous illness or even death. These harmful oxidants arc basically reactive oxygen species (ROS) and reactive nitrogen species (RNS). Among them, the majority are free radicals.
There are three sources of free radicals for a human body. Internal source includes mitochondria, inflammation, exercise, xanthine oxidase, peroxisomes, phagocytes, etc. Free radicals from internal source are actually generated from normal metabolic cycles. Part of them is used by immune system to light against the invasion of bacteria or virus. Their functions also include redox signaling, cleaning up death cells, activating and modulating some important life processes, etc. Overall, free radicals from internal source are often kept under control by the redox system. External source includes cigarette smoke, alcoholism, toxins, certain drugs, ozone, UV light, radiation, pesticides, herbicides, environmental pollutants, etc. The third source is related to physiological factors, including stress, emotion, disease conditions, etc. Free radicals from the latter two sources are usually extra burdens of the redox system and they are the roots of oxidative stress that causes health problems.
Free radicals have been implicated in the etiology of large number of major diseases, such as Alzheimer's disease, Parkinson's disease, cancers, diabetes, HIV, acne, cardiovascular disease, renal disease, hypertension, hypercholesterolemia, hyperlipidemia, rheumatoid arthritis, inflammation, pain, aging, stroke, cataract, glaucoma, age-related macular degeneration, etc. Antioxidants that can combat free radicals have drawn significant attention in past decades. Natural sources of antioxidants include fruits, vegetables and other dietary. Herbal polyphenols, flavonoids, beta-carotene, vitamin A, vitamin C, vitamin E, lipoic acid, dithiolethione, ovothiol, glutathione and melatonin are some examples of naturally occurring antioxidants. However, some problems might be encountered when naturally occurring antioxidants are directly used as drugs. Their bioavailability may not be good enough because many of them have poor solubility in water. Their antioxidant power may not precisely fit in the indication. Some polyphenols can form precipitates with proteins (enzymes) down the digestive tract, resulting in poor bioavailability and causing digestion issue.
There has been much less number of synthetic organic antioxidants so far than that of natural occurring antioxidants. Edaravonc, pirenoxine, phacolin and bendazac are some examples of synthetic organic antioxidants. These four are not approved by FDA for use as drugs in US. But they are approved for use as drugs in some other countries, even though none of them has remarkable therapeutic effects nor is a drug for major diseases. BHT(2,6-Di-ter^utyl- -methylphcnol) is another example of synthetic organic antioxidant, which is widely used as a stabilizer for storage of some organic solvents, such as THF and diethyl ether, etc., s protect them from being air-oxidized. Oltipraz, DTT (dithiothreitol), probucol and succinobucol are other examples of synthetic organic antioxidants. None of these has been approved as antioxidant drug, although oltipraz is used as a schistosomicide. But the advantages of synthetic organic antioxidants arc clear that they can be designed in such a way to enhance the bioavailability, to minimize their toxicities, to tunc in the scavenging power on free radicals, and so forth. Synthetic antioxidants can certaihly play an important role in treatment and/or prevention of major diseases thai are associated with oxidative stress.
By definition, antioxidants are a class of compounds that can deactivate reactive oxidants by fnians of being oxidized themselves. As of being readily oxidized, the organic antioxidants are often aniline-like compounds (including ifdole-like), phenol or polyphenol compounds, thiol-containing compounds and selenol-containing compounds. In order to be used as drugs, both reduced form and oxidized form of the ideal antioxidant should not have any toxicity issues. For example, phosphine compounds are known to be easily oxidized and can be good antioxidants in chemical wise. But they are ruled out as drugs due to toxicity issues.
The theory of free radicals and antioxidants related to human health is widely accepted in main stream of science worldwide. Numerous research papers have been published in large scope of scientific journals and this trend is still continuing. Positive results are reported from many vitro and vivo tests, and even reported from some early phase clinical trials. Since 1990"s. however, several strictly designed clinical trials have shown inconclusive results, no efficacy or high adverse effects on high dose of several antioxidants, casting shadows on this research area. A breakthrough is urgently needed.
PRIOR ART
1. Current Situation of Natural Antioxidants and Synthetic Antioxidants As a summary in chemistry theory, a drug-to-be molecule of organic antioxidant should first be a nitrogen-containing, oxygen-containing, sulfur-containing, or selenium-
Figure imgf000004_0001
An interesting example of synthetic phenolic antioxidant is succinobucol (AGI- 1067) of AtheroGenics, which is similar to BHT in structure as shown in Figure III.
Figure imgf000005_0001
Aspirin Salicylic acid NOSH-Aspirin
Figure V. Aspirin Related Compounds Cysteine is a sulfur-containing, naturally occurring amino acid, well known for its function in biological redox system. Its oxidized form, cystine, plays an important role in
Figure imgf000006_0001
It is worth mentioning that some interesting molecules were reported as shown below in Figure VIII (Garner, et al, US patent App. No. 20090192212). Sulfur atom is placed at allylic position, where the sulfur atom is activated and it helps form disulfide.
Figure imgf000007_0001
Figure VIII. Some Reported Dithiol-Containing Antioxidants
2. Clinical Trial Situation of Antioxidants as Investigational Drugs
Numerous studies in clinical trials have been carried out on many naturally occurring antioxidants, such as vitamin A, vitamin C, vitamin E, melatonin, beta-carotene, in treatment or prevention of a variety of diseases, such as neurodegenerative diseases, cancer, inflammation, atherosclerosis, aging, etc. No efficacy, marginal benefits or controversial results have been obtained. In some studies, vitamin A, vitamin E, and beta-carotene even leads to higher adverse effects, such as higher mortality or higher risk of certain cancers.
Synthetic antioxidants, which arc not fully explored yet, are drawing more¾ attention nowadays. Therefore, more powerful antioxidants and free radical scavengers are critically needed. Besides, other issues such as choosing appropriate biomarkers and selecting appropriate animal models for efficacy should be carefully addressed. Delicate design on drug penetration can better enhance the bioavailability of investigational drugs and thus plays important role in this invention. Since there is no antioxidant drug for major diseases being mfrketed with remarkable therapeutic effect, nor approved by FDA yet, this invention presents novel, drug-to-be molecules designed with the strongest possible power of | ioxidant and of scavenger for free radicals, with reasonable bioavailability ah ¾vi¾th no toxicity issue hopefully as this has to be further tested.
SUMMARY OF THE INVENTION
This invention is directed to novel dithiol-containing compounds which possess strongest possible capability as both scavenger for free radicals and antioxidant, their rational design, their proposed preparations by means of synthetic organic chemistry, and their potential uses in application to treatment and or prevention of major diseases associated with oxidative stress, such as Alzheimer's disease, Parkinson's disease, cancer, diabetes, HIV, acne, cardiovascular disease, renal disease, hypertension, hyperlipidemia, h y perc ho 1 est era 1 em i a . rheumatoid arthritis, inflammation, pain, aging, stroke, cataract, glaucoma, age-related macular degeneration, etc.
DESCRIPTION OF THE EMBODIMENTS OF THE INVENTION
1. Rational Design for Strongest Possible Antioxidants and Scavengers of Free Radicals
In order to be used as an antioxidant, a compound must consist of at least one functional group that can be readily oxidized. From the periodic table of the elements, the functional group of a drug-to-be organic antioxidant must consist of at least an atom of low valent nitrogen, oxygen, sulfur, or selenium. The order of antioxidant strength is selenophenol>thiophenol>aniline>phenol, based on chemistry theory. In addition, the order of antioxidant strength is thiophenol>alkyl thiol; aniline>alkyl amine, and so forth.
The strength of a free radical scavenger is not identical to its strength as an
Figure imgf000008_0001
Figure IX. Free Radical Form Of Alpha-Tocopherol (a- Vitamin E) Bond Energy:
R— S' + S— R R— S— S— R R— S— S— R 60 kcal/mol
Figure imgf000009_0001
ceary om t e ntramoecuar cyc zaton o t e t o-contanng moecue va ormng a disulfide bond. When cyclization via a disulfide bond occurs by free radical mechanism, it is favored to form a 5-membered ring. However, when cyclization occurs via non-free- radical mechanism, a 6-membered ring is favored. This is illustrated in scheme V.
Figure imgf000010_0001
Scheme V. A Novel Drug Could Re e se A Damaged Protein
Antioxidant drugs should: etter be in their "reduced forms". When quenching frees radicals, they are oxidized and become "oxidized forms". The "oxidized forms" are not active and have no more capability of quenching free radicals. Thiol and thiophenol: are the "reduced forms" of antioxidant drugs, but are unstable for storage because they are prone to air oxidation. Hence, thiol and thiophenol must be chemically protected by other functional groups in order for a drug to be stored under atmosphere. At this point, the protected one is a pro<¾g: that can release the drug as active "reduced form" in vivo where the protection group is chemically disconnected. The protection groups selected in this invention alsp adli as penetration enhancer in order for a drug to be better delivered. In addition, the protection groups must have no toxicity issue.
As a Summary, each novel molecule in this invention consists of at least two thiol groups. When oxidized, the sterical configuration allow s them to fonn a 5 or 6-membered ring with a new disulfide bond in the ring. The thiol group is covalently single-bonded with a carbon atom located on aromatic ring, at benzyl ie position of aromatic ring, or at allylic position. In chemistry theory, thiophenol is stronger antioxidant than alkyl thiol. Based on these rules for design, there are 12 basic categories (A-L) of novel dithiol- containing antioxidants, as shown in Figure 1 of drawings.
The variable part is the matrix that can be either regular aromatic ring or aromatic heterocyclic ring, with any possible combinations. Therefore, a large variety of new compounds are designed, with consideration of drug delivery that usually requires drug compounds to be amph i pat h i c . I "un ct iona 1 groups that are covalently bonded with thiols act as not only protection group, but also penetration enhancer for drug delivery. These functional groups include, but not limited to, amino acid, vitamin B's, choline, dopamine, EDTA, carbohydrate, nucleic base, citric acid, succinic acid, heterocycles, etc. The novel, drug-to-be molecules are numbered in Arabic hereafter unless otherwise notified.
Aspirin is probably the most popular drug in history. It is widely used in many indications as pain-killer, anti-inflammation, fever-reducer, preventing stroke and heart attack, etc. Expanded applications of aspirin in treatment and/or prevention of Alzheimer's disease, cancer and diabetes are under wide studies in recent years. Compound 1 is the mimic of aspirin (Figure 2 of drawings), as a drug candidate in this invention. Compound la, the mimic of salicylic acid, would he the active form of compound 1 in vivo. As lc is a known compound, compound lb w ould reasonably be the oxidized form of compound la. Therefore, compound 1, as a new chemical entity and pro-drug of novel antioxidant, would be promising to beat aspirin in many indications With different protection groups, more drug-to-be molecules of aspirin mimics are depicted (Figure 3 of drawings). After disconnection of protection group in vivo and being oxidized when quenching free radicals, compounds 3-11 would offer compound lc as the oxidized form in common. There arc more examples of aspirin mimics with extended structure alteration (Figure 4 of drawings).
Vitamin E is a naturally occurring antioxidant and served as an important dietary nutrition. Vitamin E family has two groups: tocopherols and tocotrienols. Each group has four forms: alpha (a), beta (β), gamma (γ), an Selta (δ). The capability of vitamin E as antioxidant and free radical scavenger is ihferi6r to that of novel drug molecules in this invention. Besides, its bioavailability if poor due to low solubility in water. Some novel designs of vitamin E mimics arc depicted (Figure 5 of drawings). There are more novel molecules of vitamin li mimics with extended structure alteration (Figure 6 of draw ings).
1.8-I)ithionaphthalene represents a class of most powerful scavengers for free radicals in this invention, as both thiols are thiophenol-like and it forms a 5-mcmbcrcd ring when oxidized. Novel drug molecules on skeleton of 1.8-dithionaphthaleno with di ITerent protection i sjiips are depicted (Figure 7 of drawings).
Vitamin B6 (pyridoxine) and vitamin B3 (niacin) arc water-soluble vitamins. Both play essential roles in many important metabolic processes. Some novel designs of their mimics with different protection groups are depicted ( Figure 8 of drawings). They are similar to those molecules in Figure 3 and Figure 4 of drawings. Instead of benzene matrix, these are on pyridine matrix. Some novel molecules on pyrimidine or pyrazine matrix are also depicted (Figure 9 of drawings).
Folic acid (vitamin B9) is an important nutrition for embryo development. In the case of cancer indication, cancer cells need high amount o folic acid for high grow th rate. This may shed light for folic acid mimics to selectively deliver drug to cancer cells. Some novel molecules of folic acid mimics arc depicted (Figure 10 of drawings).
Melatonin is a hormone secreted by the pineal gland in the brain. It helps regulate sleep-wake cycle. It is also served as antioxidant according to some publications. Some novel molecules of melatonin mimics are depicted ( Figure 11 of draw ings).
Riboflavin (vitamin B2) is a water-soluble vitamin and is required for many cellular processes. Some novel molecules of its mimics are depicted (Figure 12 of drawings). The heterocyclic part of riboflavin is retained for the sake of drug delivery. For each of basic styles in figure 1 of drawings, numerous molecules can be drawn. For a flavor of that, several novel compounds are depicted (Figure 13 and Figure 14 of drawings). The mimics of some naturally occurring products outlined above can certainly play a key role in this invention. Molecular structure optimization of the numbered compounds can be made based on the data feedback from their pre-clinical tests, such as efficacy, ADME, DMPK, etc. Good drug candidates will be moved forward to clinical trial and beyond.
2. Uses of the Novel Antioxidants in Treatment and or Prevention of Major Diseases
Free radical oxidation has been reported to associate with following indications, Alzheimer's disease, Parkinson's disease, diabetes, cardiovascular disease, cancer, renal disease, hypertension, hypercholesterolemia, hyperlipidcmia, rheumatoid arthritis, pain, inflammation, stroke, HIV, aging, acne, cataract, age-related macular degeneration, glaucoma, etc. The potential application of novel: drug molecules in this invention could be applied to treatment and/or prevent ion of these indications.
Age-related cataract is cloudiness of lens that consists of proteins and water. The proteins in lens are transparent in normal array. When oxidized by free radicals, the lens proteins become cross-linked by forming disulfide bonds, leading to structure change of the proteins and distortion of protein array in lens, and resulting in permanent cloudiness. Currently, there is no medication available to cure cataract. Surgical removal opaque lens and implanting artificial lens is the only therapy for cataract patients. Surgery therapy is simple, but relatively costly.
According to thiol-disulfide exchange in scheme IV and scheme V, oxidative damage of lens protein could be reversed to normal lens protein. Thus, novel drug molecules in this invention as the highest powerful scavengers of free radicals could have highly promising therapeutic effects in both treatment and prevention of age-related cataract. The cornea barrier is a challenger for drug delivery of eye drop medication. This issue would be addressed by several novel drug molecules in this invention designed as amphipathic compounds.
Alzheimer's disease is caused by Sclerosis of beta-amyloid (peptide) and/or fibrosis of tau protein in the brain. Free radical oxidation is a prime suspect for these protein tangles. There is currently no therapy for Alzheimer's disease. Therefore, there is an urgently need to have a drug to prevent this disease, to stop the progress of this disease, or even to cure this disease.
Since sclerosis of bet a-amy 1 oi d ( pept i de ) or fibrosis of tau protein in the brain is highly ascribed to free radical oxidation, novel drug molecules in this invention possessing the highest pow erful scavengers of free radicals could have promising therapeutic effects in both treatment and prevention of Alzheimer's disease. Blood-brain barrier is a challenger for drug delivery of brain medication. This issue would be addressed by several novel drug molecules in this invention designed with moiety of choline, dopamine, amino acids, etc. Similar applications could be for Parkinson's disease and other neurodegenerative diseases associated with oxidative stress.
Low density lipoprotein (LDL) is prone to free radical oxidation on its lipid part. The oxidized LDL can become plaques and hard to remove, leading to narrower blood vessel, causing ischemic stroke and cardiovascular diseases. The oxidized lipids are the suspected causes of inflammation. The novel drug molecules in this invention possessing the highest powerful scavengers of free radicals would find applications in prevention and/or treatment of rheumatoid arthritis, ischemic stroke and relevant cardiovascular diseases, such as atherosclerosis, hyperlipidemia, heart attack, etc.
Oxidative stress has been associated ith many cancers. The uses of antioxidants in prevention and/or treatment of cancers hav e been w idely studied and published. But, there is still no major breakthrough yet. Some novel antioxidant molecules in this invention, especially novel molecules of folic acid mimics, would find applications in prevention and/or treatment of cancers, such as liver cancer, lung cancer, pancreatic cancer, stomach cancer, breast cancer, prostate cancer, colon cancer, etc.
3. Chemical Synthesis of the Novel Antioxidant Molecules in This Invention
Chemical transformations of relevant functional groups have been w ell reported from reliable sources such as JACS and Organic Synthesis. Several typical chemical conversions are shown in scheme 1 of drawings. Therefore, rational designs for synthetic routes of nej¼ehemical Entities in this invention are considered as highly feasible.
Examples of chemical synthesis of novel antioxidants in this invention are given below Typical synthetic routes of novel compounds 1 and 74 in this invention have been show n in sctifeiie 2 of drawings. Starting material thiophenol is commercially available, which can also be synthesized from bromobenzene via Grignard reaction as reported. Lithiation of thiophenol gives ortho-directed lithiation intermediate. The lithiated intermediate reacts with carbon disulfide, followed by acctylation to afford compound 1. Pyridoxine (vitamin B6) treated with thionyl chloride could give di-chloride intermediate as shown in scheme 2 of drawings. The di-chloride intermediate could efficiently react with compound 1 to afford compound 74 in the presence of sodium bicarbonate and phase transfer catalyst (PTC) such as tetrabuty lam mon i um bromide (TBAB).

Claims

NOVEL SYNTHETIC ANTIOXIDANTS AND THEIR USES(Inventor: Yansong Lu; Date: 4-15-2013; email: yansonglu(¾faotmail .com) CLAIMS What is claimed is:
1. The novel molecules comprising at least two thiol (-SH) groups that when oxidized, can form an intramolecular 5 or 6-membered ring via a disulfide bond.
2. The thiol group of claim 1 wherein is considered as a regular thiol thiophenol (-SH), carbodithioic acid (-CSSH), or thiolcajboxylic acid (-COSH).
3. The thiol group of claim 1 wherein is ep¾al¾ntly single-bonded with a carbon atom located on aromatic ring, at ben/ylic position of aromatic ring, or at allylic position.
4. The aromatic ring of claim : w¾erein includes, but not limited to, benzene, diphenylene, naphthalene, phcnanthreiie, apihracene, any aromatic heterocyclic ring, and any possible combination of them.
5. The thiol! group (-SU ) of claim 1 wherein may be chemically protected by forming a covalcnt bond with another function group including, but not limited to acetyl (-Ac), succinic acid, amt|no acid, vitamin B's, choline, dopamine, EDTA, carbohydrate, nucleic base, citric aci|? heterocyclics, etc. for the purpose of drug delivery in vivo and drug storage.
6. The novel molecules of above claims wherein may comprise other moieties including, but not limited to, carbohydrate, nucleic base, amino acid, citric acid, EDTA, building blocks of vitamins, etc., as penetration enhancer to increase bioavailability.
7. The compounds of above claims wherein may be used as dietary supplements and active pharmaceutical ingredients for indications associated with oxidative stress, which include, but not limited to, HIV, stroke, Alzheimer's disease, Parkinson's disease, diabetes, cardiovascular disease, cancer, renal disease, hypertension, cataract, glaucoma, age-related macular degeneration, aging, acne, pain, inflammation, hypercholesterolemia, hyperlipidemia. rheumatoid arthritis, etc.
8. The novel molecules of above claims wherein may be synthesized by means of synthetic organic chemistry.
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