Synthetic antioxidants and their uses

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.

Claims

1. A compound comprising at least one pair of functional groups that consist of one functional group as thiol (SH), optionally acylated, and another one as either carbodithioic acid (CSSH) or carbothioic acid (COSH), which when oxidized can form an intramolecular 5 or 6-membered ring via a disulfide bond, wherein said one pair functional groups are each optionally protected by an independently selected protecting group that is removable under physiological conditions for the purpose of drug delivery.

2. The compound of claim 1, wherein each of the pair of functional groups is covalently single-bonded with a carbon atom located on an aromatic ring that is selected from the group consisting of benzene, diphenylene, naphthalene, phenanthrene, anthracene, aromatic heterocyclic rings and combinations thereof.

3. The compound of claim 1, wherein each of the pair of functional groups is optionally protected by forming a covalent bond with another functional group or molecular moiety independently selected from the group consisting of acetyl (Ac), succinic acid, amino acid, vitamin B's, choline, dopamine, EDTA, carbohydrate, nucleic base, citric acid, and heterocycles for the purpose of drug delivery in vivo and drug storage.

4. The compound of claim 1, further comprising one or more other moieties that are independently selected from the group consisting of carbohydrate, nucleic base, amino acid, citric acid, EDTA, and building blocks of vitamins, as a penetration enhancer to increase bioavailability.

5. The compound of claim 1, wherein the compound is synthesized by means of synthetic organic chemistry.

6. A pharmaceutical or dietary supplement composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

7. The pharmaceutical or dietary supplement composition of claim 6, wherein the compound is selected from the group consisting of: ##STR00017##

8. The pharmaceutical or dietary supplement composition of claim 6, wherein the compound is selected from the group consisting of: ##STR00018## ##STR00019## ##STR00020## ##STR00021## ##STR00022## ##STR00023##

9. The compound of claim 1 selected from the group consisting of: ##STR00024##

10. The compound of claim 1 selected from the group consisting of: ##STR00025## ##STR00026## ##STR00027## ##STR00028## ##STR00029## ##STR00030##

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 illustrates some basic styles of novel dithiol-containing antioxidants.

(2) FIG. 2 illustrates some novel aspirin mimics.

(3) FIG. 3 illustrates novel aspirin mimics with different protection groups.

(4) FIG. 4 illustrates novel aspirin mimics with some extended structure alteration.

(5) FIG. 5 illustrates novel vitamin E mimics with different protection groups.

(6) FIG. 6 illustrates novel vitamin E mimics with some extended structure alteration.

(7) FIG. 7 illustrates novel drug molecules on the naphthalene matrix.

(8) FIG. 8 illustrates novel mimics of pyridoxine and niacin with some extended structure alteration.

(9) FIG. 9 illustrates some novel molecules on the pyrimidine or pyrazine matrix.

(10) FIG. 10 illustrates novel folic acid (vitamin B9) mimics with some extended structure alteration.

(11) FIG. 11 illustrates novel melatonin mimics with some extended structure alteration.

(12) FIG. 12 illustrates novel riboflavin (vitamin B2) mimics with some extended structure alteration.

(13) FIG. 13 illustrates some novel molecules with other matrices.

(14) FIG. 14 illustrates some novel molecules with dimer or trimer of the antioxidants.

DESCRIPTION OF THE EMBODIMENTS OF THE INVENTION

(15) 1. Rational Design for Strongest Possible Antioxidants and Scavengers of Free Radicals

(16) 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.

(17) The strength of a free radical scavenger is not identical to its strength as an antioxidant, even though they are relevant. Three features of free radical chemistry are initiation, propagation and termination. In initiation stage, free radical can be generated by heat, light, radiation, metabolic cycles or some certain chemical reagents. Free radical can propagate by means of electron transfer or hydrogen radical transfer. In propagation stage, the total number of free radicals is constant, with some disappeared and some emerged at the same time. Scheme I shows the propagation of free radical. Termination of free radicals can be done by reacting one free radical with another to form a coupling compound. In this stage, free radicals disappear. Scheme II shows the termination of two free radicals by forming a coupling compound.

(18) ##STR00009##

(19) Although the reactivity of each free radical in scheme I is diminishing down the track, they are still free radicals and each of them is still capable of taking in an electron or a hydrogen radical from other vulnerable molecules. Therefore, each of them is considered as pro-oxidant, as they can still oxidize other molecules by taking in electrons or hydrogen radicals. This is exactly what happened to vitamin E, vitamin A or beta-carotene when they were used in clinical trials to against some certain cancers. For example, when a molecule of vitamin E deactivates a harmful free radical, itself becomes a free radical as shown below. The free radical form of vitamin E is a pro-oxidant and is still capable of doing harm to important biological macromolecules such as proteins, DNA and lipids. This can well explain why higher rate of some certain cancers were observed when vitamin E, vitamin A or beta-carotene were used in clinical trials. These clinical trial data can, from another hand, verify that the hypothesis that free radicals can cause cancers by damaging DNA and/or other important biological macromolecules is true. Free radical scavengers as antioxidant drugs, therefore, are no doubt going to work. The key is how to efficiently terminate free radicals, so as to avoid the lengthy propagation of free radicals. This prompts innovative designs for novel drug molecules in this invention.

(20) ##STR00010##

(21) ##STR00011##

(22) From scheme II, bond energy of peroxide is the lowest. This means that the reaction can readily go to the left side. Actually, peroxide can easily undergo homolytic cleavage generating two free radicals. Besides, bond energy of disulfide is higher than that of diselenide. It means that thiol is a more powerful scavenger of free radicals than selenol, although selenol is a stronger antioxidant than thiol. In addition, NN single bond energy is 38 kcal/mol that is not shown in scheme H. Thus, disulfide has the highest bond energy among all interested functional groups and thiol is hence the most powerful scavenger of free radicals among them.

(23) ##STR00012##

(24) According to the theory of chemical kinetics, a dithiol-containing molecule (drug) has a much faster reaction rate than that of mono thiol-containing molecule, to form the disulfide yin scheme II, especially when it can form a 5-membered ring via a disulfide bond. Besides, one dithiol-containing molecule (drug) can efficiently terminate two free radicals as illustrated in scheme III.

(25) Oxidative damage of protein by free radicals is mainly ascribed to the formation of cross-linking via disulfide bonds. The structural alteration caused by the cross-linking leads to dysfunction or malfunction of the protein. In addition, it is well known that thiol-disulfide exchange is reversible (scheme IV). Therefore, it is possible to use an appropriate thiol-containing reagent (drug) to convert disulfide of damaged protein back to thiols of normal protein and thus to fix the oxidative damage of the protein.

(26) ##STR00013##

(27) Based on chemical kinetics, a dithiol-containing molecule (drug) has maximum driving force to push the equilibrium to the right side in scheme IV. The driving force is clearly from the intramolecular cyclization of the dithiol-containing molecule via forming 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.

(28) ##STR00014##

(29) Antioxidant drugs should better Abe in their reduced forms. When quenching free 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 prodrug 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 also act as penetration enhancer in order for a drug to be better delivered. In addition, the protection groups must have no toxicity issue.

(30) As a summary, each novel molecule in this invention consists of at least two thiol groups. When oxidized, the sterical configuration allows them to form 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 benzylic 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 FIG. 1 of drawings.

(31) 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 amphipathic. Functional 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.

(32) 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 (FIG. 2 of drawings), as a drug candidate in this invention. Compound 1a, the mimic of salicylic acid, would be the active form of compound 1 in vivo. As 1c is a known compound, compound 1b would reasonably be the oxidized form of compound 1a. 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 (FIG. 3 of drawings). After disconnection of protection group in vivo and being oxidized when quenching free radicals, compounds 3-11 would offer compound 1c as the oxidized form in common. There are more examples of aspirin mimics with extended structure alteration (FIG. 4 of drawings).

(33) 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 (), beta (), gamma (), and delta (). The capability of vitamin E as antioxidant and free radical scavenger is inferior to that of novel drug molecules in this invention. Besides, its bioavailability is poor due to low solubility in water. Some novel designs of vitamin E mimics rare depicted (FIG. 5 of drawings). There are more novel molecules of vitamin E mimics with extended structure alteration (FIG. 6 of drawings).

(34) 1,8-Dithionaphthalene represents a class of most powerful scavengers for free radicals in this invention, as both thiols are thiophenol-like and it forms a 5-membered ring when oxidized. Novel drug molecules on skeleton of 1,8-dithionaphthalene with different protection groups are depicted (FIG. 7 of drawings).

(35) Vitamin B6 (pyridoxine) and vitamin B3 (niacin) are water-soluble vitamins. Both play essential roles in many important metabolic processes. Some novel designs of their mimics with different protection groups are depicted (FIG. 8 of drawings). They are similar to those molecules in FIG. 3 and FIG. 4 of drawings. Instead of benzene matrix, these are on pyridine matrix. Some novel molecules on pyrimidine or pyrazine matrix are also depicted (FIG. 9 of drawings).

(36) Folic acid (vitamin B9) is an important nutrition for embryo development. In the case of cancer indication, cancer cells need high amount of folic acid for high growth rate. This may shed light for folic acid mimics to selectively deliver drug to cancer cells. Some novel molecules of folic acid mimics are depicted (FIG. 10 of drawings).

(37) 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 (FIG. 11 of drawings).

(38) Riboflavin (vitamin B2) is a water-soluble vitamin and is required for many cellular processes. Some novel molecules of its mimics are depicted (FIG. 12 of drawings). The heterocyclic part of riboflavin is retained for the sake of drug delivery.

(39) For each of basic styles in FIG. 1 of drawings, numerous molecules can be drawn. For a flavor of that, several novel compounds are depicted (FIG. 13 and FIG. 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.

(40) 2. Uses of the Novel Antioxidants in Treatment and/or Prevention of Major Diseases

(41) 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, hyperlipidemia, 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 prevention of these indications.

(42) 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 of opaque lens and implanting artificial lens is the only therapy for cataract patients. Surgery therapy is simple, but relatively costly.

(43) 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.

(44) 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.

(45) Since sclerosis of beta-amyloid (peptide) or fibrosis of tau protein in the brain is highly ascribed to free radical, oxidation, novel drug molecules in this invention possessing the highest powerful 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.

(46) 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.

(47) Oxidative stress has been associated with many cancers. The uses of antioxidants in prevention and/or treatment of cancers have been widely 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.

(48) 3. Chemical Synthesis of the Novel Antioxidant Molecules in this Invention

(49) Chemical transformations of relevant functional groups have been well reported from reliable sources such as JACS and Organic Synthesis. Several typical chemical conversions are shown in scheme VI. Therefore, rational designs for synthetic routes of new chemical entities in this invention are considered as highly feasible.

(50) ##STR00015##

(51) 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 shown in scheme VII.

(52) ##STR00016##

(53) 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 acetylation to afford compound 1. Pyridoxine (vitamin B6) treated with thionyl chloride could give di-chloride intermediate as shown in scheme VII. 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 tetrabutylammonium bromide (TBAB).