ANTIOXIDANT POLYMERS CONTAINING [1,2]-DITmOLANE MOIETIES

AND USES THEREOF

FIELD OF INVENTION The present invention relates to dithiolane derivatives and antioxidant polymers containing dithiolane moieties that are capable of acting as scavengers of free radicals, metals and reactive oxygen species (ROS) and/or are capable of allowing the regeneration of endogenous antioxidants or entities which trap the ROS.

BACKGROUND

All publications herein are incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. The following description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.

Molecules containing a dithiolane moiety are widely investigated due to their antioxidant properties. α-Lipoic acid (thioctic acid, 1 ,2-dithiolane-3-pentanoic acid), which has a dithiolane ring in its molecule, is a widely distributed natural substance which was originally discovered as a growth factor. Physiologically, it acts as a coenzyme of the oxidative decarboxylation of α-keto carboxylic acid (e.g., pyruvates) and as an antioxidant, and it is able to regenerate vitamin C, vitamin E, glutathione and coenzyme Q10. In pathological conditions, lipoic acid is applied in the treatment of diabetic polyneuropathy, liver cirrhosis and metal intoxications.

α-Lipoic acid Dihydrolipoic acid

Lipoic acid and dihydrolipoic acid are capable of trapping a number of radicals both in a lipid and in an aqueous environment. Lipoic acid and dihydrolipoic acid act as antioxidants not only by direct radical trapping and/or metal chelation but also by

recycling other antioxidants (e.g., vitamin C, vitamin E) and by reducing glutathione, which in turn recycles vitamin E. The two thiol groups present in the [1 ,2]-dithiolane ring system confer upon it a unique antioxidant potential. The disulfides with a cyclic five-member ring such as lipoic acid have been found to be more effective in reductive and/or nucleophilic attack than open-chain derivatives such as cystine or glutathione.

The antioxidant potential of a compound may be evaluated based on the properties such as (1) specificity of free radical scavenging, (2) interaction with other antioxidants, (3) metal-chelating activity, (4) effects on gene expression, (5) absorption and bioavailability, (6) location (in aqueous or membrane domains, or both), and (7) ability to repair oxidative damage (Packer et al., FREE RADICAL BIOLOGY & MEDICINE. 19(2):227-250, 1995). According to the above criteria, the [1 ,2]- dithiolane containing lipoic acid/dihydrolipoic acid redox system has been regarded as a universal antioxidant. There have been many attempts to develop lipoic acid derivatives or complexes having antioxidant activity. U.S. Patent Nos. 6,090,842; 6,013,663; 6,117,899; 6,127,394; 6,150,358; 6,204,288, 6,235,772; 6,288,106; 6,353,011 ; 6,369,098; 6,387,945; 6,605,637; 6,887,891 ; 6,900,338; and 6,936,715 are some examples. In many other U.S. patents, the natural and synthetic lipoic acid derivatives and their metabolites are disclosed for use in preventing skin aging and in the treatment of free radical mediated diseases, including inflammatory, proliferative, neurodegenerative, metabolic and infectious diseases.

Inhibitory activity on NO-synthase and trapping the reactive oxygen species (ROS) Various conditions or disease conditions have demonstrated a potential role of nitric oxide (NO) and the ROS's and the metabolism of glutathione in their physiopathology. Conditions or disease conditions where nitrogen monoxide and the metabolism of glutathione as well as the redox status of thiol groups are involved include but are not limited to: cardiovascular and cerebrovascular disorders (e.g., atherosclerosis, migraine, arterial hypertension, septic shock, ischemic or hemorrhagic cardiac or cerebral infarctions, ischemias and thromboses); disorders of

the central or peripheral nervous system (e.g., neurodegenerative nervous system); neurodegenerative diseases including cerebral infarctions, sub-arachnoid hemorrhaging, aging, senile dementias (e.g., Alzheimer's disease), Huntington's chorea, Parkinson's disease, prion disease (e.g., Creutzfeld Jacob disease), amyotrophic lateral sclerosis, pain, cerebral and spinal cord traumas, addiction to opiates, alcohol and addictive substances, erective and reproductive disorders, cognitive disorders, encephalopathies, encephalopathies of viral or toxic origin, depression, anxiety, schizophrenia, epilepsy, sleeping disorders, eating disorders (e.g., anorexia, bulimia); disorders of the skeletal muscle and neuromuscular joints (e.g., myopathy, myositis), cutaneous diseases; proliferative and inflammatory diseases (e.g., atherosclerosis), pulmonary hypertension, respiratory distress, glomerulonephritis, cataracts, portal hypertension, psoriasis and rheumatoid arthritis, fibroses, amyloidoses, inflammations of the gastro-intestinal system (e.g., colitis, Crohn's disease) or of the pulmonary system and airways (e.g., asthma, sinusitis, rhinitis) as well as contact or delayed hypersensitivities; organ transplantation; autoimmune and viral diseases (e.g., lupus, AIDS, parasitic and viral infections), diabetes and its complications (e.g., retinopathies, nephropathies and polyneuropathies, multiple sclerosis, myopathies); cancer; autosomal genetic diseases (e.g., Unverricht-Lundborg disease); neurological diseases associated with intoxications (e.g., cadmium poisoning, inhalation of n-hexane, pesticides, herbicides), associated with treatments (e.g., radiotherapy) or disorders of genetic origin (e.g., Wilson's disease); and impotence linked to diabetes.

These conditions and disease conditions are characterized by an excessive production or a dysfunction of nitrogen monoxide and/or the metabolism of glutathione and of the redox status of the thiol groups (Duncan and Heales, Nitric Oxide And Neurological Disorders, MOLECULAR ASPECTS OF MEDICINE. 26:67-96, 2005; Kerwin et al., Nitric Oxide: A New Paradigm For Second Messengers, J. MED. CHEM. 38:4343-4362, 1995; Packer et al., FREE RADICAL BIOLOGY & MEDICINE. 19:227-250, 1995). U.S. Pat. Nos. 6,605,637, 6,887,891 , and 6,936,715 disclose that lipoic acid derivatives inhibit the activity of NO-synthase enzymes producing nitrogen monoxide NO and regenerate endogenous antioxidants which trap the ROS and which intervene in a more general fashion in the redox status of thiol groups. U.S.

Pat. Nos. 5,693,664, 5,948,810, and 6,884,420 disclose the use of racemic α-lipoic acid or their metabolites, salts, amides or esters for the synthesis of drugs for the treatment of diabetes mellitus of types I and II. U.S. Pat. No. 5,925,668 discloses a method of treating free radical mediated diseases, and/or reducing the symptoms associated with such diseases whereby the compounds with antioxidant activity contain 1 ,2-dithiolane, reduced or oxidized forms. U.S. Pat. No. 6,251 ,935 discloses methods for the prevention or treatment of migraine comprising the administration of an active ingredient selected from the group consisting of racemic alpha-lipoic acid, enantiomers and pharmaceutically acceptable salts, amides, esters or thioesters thereof. U.S. Pat. Nos. 6,472,432 and 6,586,472 disclose the treatment of a chronic inflammatory disorder, rosacea, by application of a composition containing lipoic acid and/or lipoic acid derivatives. There is also strong evidence that the neuroprotective effects of lipoic acid and dihydrolipoic acid are mediated by antioxidant and free radical scavenging mechanisms (Packer et al., FREE RADICAL BIOLOGY & MEDICINE. 22:359-378, 1997).

Topical application and cosmetic preparation

Ultraviolet light can produce reactive oxygen species (ROS) that damage the skin leading to the premature aging of the skin. ROS are a collection of reactive free radicals produced from the oxygen molecules, including singlet oxygen, the superoxide radical, hydrogen peroxide, and the hydroxyl radical, as well as the reaction products produced by these free radicals. These ROS react with other molecules and generate a cascade of harmful free radical reactions in the skin.

U.S. Pat. Nos. 5,709,868 and 6,752,999 disclose methods for the prevention and/or treatment of skin damage, particularly inflammation and aging whereby a composition containing lipoic acid/or lipoic acid derivatives are topically applied to affected skin areas. U.S. Pat. Nos. 5,965,618 and 6,955,816 disclose compositions and methods for the treatment and inhibition of scar tissue based on topical application of compositions containing lipoic acid and/or lipoic acid derivatives to scars and to injured skin sites. U.S. Pat. No. 6,365,623 discloses the treatment of active acne and acneiform scars by topical application of a composition containing lipoic acid and/or a lipoic acid derivative.

Cancer therapy

U.S. Pat. Nos. 5,035,878 and 5,294,430 disclose that dithiocarbamates, which have antioxidant properties, can reverse the damage to the blood-forming function of the bone marrow (myelesuppression) caused by treatment with antineoplastic agents. U.S. Pat. Nos. 6,284,786, 6,448,287, and 6,951 ,887 disclose methods of cancer therapy using lipoic acid as a therapeutic agent administered in combination with ascorbic acid. U.S. Pat. No. 7,071 ,158 discloses that antioxidants increase the cytotoxicity of antineoplastic agents to abnormally proliferating cells and decrease the toxicity of antineoplastic agents to normal cells.

However, many of the currently available oral formulations have a low bioavailability due to incomplete absorption and first-pass metabolism. Rapid degradation of antioxidants in the body fluid and elimination of antioxidants from the body further decreases the beneficial effects of antioxidants. Further, some antioxidants may be limited by their stoichiometric quantities; for example it has been postulated that antioxidant potency of vitamins such as C and E is limited because they work as scavengers of existing excess reactive species. (Johanse et al. Oxidative stress and the use of antioxidants in diabetes: Linking basic science to clinical practice, CARDIOVASCULAR DIABETOLOGY. 4:5, 2005) Thus, there is a need in the art to overcome one or more of these limitations. There is also a need for useful compounds for the treatment of conditions or disease conditions wherein the potential role of NO and the ROS's and the metabolism of glutathione has been demonstrated in their physiopathology. The inventive [1 ,2]-dithiolane derivatives, oligomers and/or polymers thereof described herein may be useful for such treatments. The inventive [1 ,2]-dithiolane derivatives and oligomers and/or polymers thereof may be useful for to treat or delay the onset of conditions and disease conditions caused by oxidative damage (e.g., skin aging, wrinkle formation), for the protection of skin from damage caused by ultraviolet radiation and dessication, and for cancer therapy. The inventive polymers that are sensitive to an acidic environment enable the rate of erosion to be associated with the rate of release of a therapeutic agent, which may be controlled by their molecular structures.

BRIEF DESCRIPTION OF THE FIGURE

Exemplary embodiments are illustrated in referenced figure. It is intended that the embodiments and figure disclosed herein are to be considered illustrative rather than restrictive.

Figure 1 depicts hydrolytic degradation of polymers in accordance with various embodiments of the present invention.

DESCRIPTION OF THE INVENTION All references cited herein are incorporated by reference in their entirety as though fully set forth. Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Singleton et al., Dictionary of Microbiology and Molecular Biology 3 ^rd ed., J. Wiley & Sons (New York, NY 2001); March, Advanced Organic Chemistry Reactions, Mechanisms and Structure 5 ^th ed, J. Wiley & Sons (New York, NY 2001); and Sambrook and Russel, Molecular Cloning: A Laboratory Manual 3rd ed., Cold Spring Harbor Laboratory Press (Cold Spring Harbor, NY 2001), provide one skilled in the art with a general guide to many of the terms used in the present application. The contents of U.S. Provisional Application Serial Nos. 60/892,360

60/892,370, 60/892,376, and 60/892,383, all filed on March 1 , 2007, are herein incorporated by reference in their entirety as though fully set forth.

One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. Indeed, the present invention is in no way limited to the methods and materials described. For purposes of the present invention, the following terms are defined below.

"Conditions" and "disease conditions," as used herein may include, but are in no way limited to conditions or disease conditions wherein the potential role of NO, ROS's or the metabolism of glutathione have been demonstrated in their physiopathology, conditions or disease conditions caused by oxidative damage, and

any form of neoplastic cell growth and proliferation, whether malignant or benign, pre-cancerous and cancerous cells and tissues.

"Pharmaceutical" and "drug," as used herein, refer to any substance used internally or externally as a medicine for the treatment, cure or prevention of a disease or disorder, even if the treatment, cure or prevention of the disease or disorder is ultimately unsuccessful.

"Polymeric antioxidant" as used herein refers to a polymer that contains a [1 ,2]-dithiolane moiety as a monomeric repeating unit or a polymer that contains a [1 ,2]-dithiolane moiety that is covalently attached to the polymer backbone, and reduces the oxidation of an oxidizable compound under physiological condition.

"Antineoplastic agents," as used herein, refer to any substance that decreases abnormal cell proliferation.

"Therapeutically effective amount" as used herein refers to that amount which is capable of achieving beneficial results in a patient with a condition or a disease condition in which treatment is sought. A therapeutically effective amount can be determined on an individual basis and will be based, at least in part, on consideration of the physiological characteristics of the mammal, the type of delivery system or therapeutic technique used and the time of administration relative to the progression of the disease. "Treatment" and "treating," as used herein refer to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent, slow down and/or lessen the disease even if the treatment is ultimately unsuccessful.

"Acetal" as used herein refers to a diether in which both ether oxygen atoms are bound to the same carbon.

Various embodiments of the present invention provide for antioxidant polymers that contain [1 ,2]-dithiolane moieties. In one embodiment, the antioxidant polymers of the present invention are capable of acting as scavengers of free radicals. In another embodiment, the antioxidant polymers of the present invention are capable of serving as a vehicle for the delivery of pharmaceutical and biological therapies.

In one embodiment, the present invention provides for an antioxidant [1 ,2]- dithiolane derivative. In another embodiment, the present invention provides for an oligomer comprising two or more antioxidant [1 ,2]-dithiolane derivative. In another embodiment, the present invention provides for a polymer comprising antioxidant [1 ,2]-dithiolane derivatives. The [1 ,2]-dithiolane derivative, oligomer thereof or polymer thereof may be biodegradable.

Additional embodiments of the present invention provide for methods of synthesizing the antioxidant polymers of the present invention.

Further embodiments of the present invention provide for methods of using the antioxidant polymers of the present invention. In one embodiment, the antioxidant polymers are used for treating conditions or disease conditions that are caused by oxidative stress or other free radical mediated diseases or disease conditions.

In a particular embodiment, the antioxidant polymer is used to treat skin inflammation or aging mediated by free radicals. The method comprises providing a composition comprising a [1,2]-dithiolane derivative, an oligomer thereof, a polymer thereof, or combinations thereof, and administering to skin areas in need of treatment a therapeutically effective amount of the composition. In one embodiment, the composition further comprises a pharmaceutically acceptable or dermatologically acceptable carrier.

In another embodiment, the antioxidant polymers are used in the preparation of antioxidant particulate delivery vehicles for therapeutic agents. In a particular embodiment, the antioxidant polymers are used as a gene delivery vehicle to carry and deliver genetic material to a subject. The genetic material may be DNA or RNA. The antioxidant polymers may also be used as a carrier for peptides or proteins; for example, for use in vaccination therapies.

In another embodiment, the antioxidant polymer may be used as a carrier of a therapeutic agent. In one embodiment, the therapeutic agent is a chemotherapeutic agent that is useful for cancer treatment. Another embodiment of the present invention provides for a method to enhance the cytotoxicity of an antineoplastic drug for treatment of a disorder of abnormal cell proliferation. The method comprises providing a composition

comprising a [1 ,2]-dithiolane derivative, an oligomer thereof, a polymer thereof or combinations thereof; administering a therapeutically effective amount of the antineoplastic drug to a subject in need of the treatment; and administering a therapeutically effective amount of the composition. In one embodiment, the antineoplastic drug is encapsulated within the composition. Antineoplastic drugs are known to one skilled in the art. Examples include but are not limited to, paclitaxel, camptothecin, oxaliplatin and temozolomide.

Polymers as macromolecular antioxidant One aspect of this invention relates to the syntheses and uses of compounds containing dithiolane rings as monomers that are polymerized into biodegradable antioxidant polymers. The monomers may be polymerized via biodegradable ester bond or acetal bond, which are susceptible to hydrolytic degradation. Upon variation of the monomers, polymers with varying hydrophobicity may be prepared. Water- soluble polymers may be used as the macromolecular antioxidant component of injectable pharmaceutical formulations. Hydrophobic polymers may be used for the preparation of antioxidant nanoparticles or microparticles that, upon administration, circulate through the body for a prolonged period of time and thus provide controlled, sustained release of the small molecular antioxidants. These antioxidants may be delivered to areas of the body including but not limited to tissue, brain, and cell.

Polymers as delivery devices

The biodegradable antioxidant polymers of the present invention may be used as pharmaceutical and/or drug delivery vehicles to deliver small molecules, peptides, oligonucleotides, polynucleotides, proteins, antigens, chemotherapeutics, and the like, to tissues, organs, and cells.

The inventive antioxidant polymers comprise multiple [1 ,2]-dithiolane groups with universal antioxidant properties. In one embodiment, the polymer is degraded under in vivo conditions over a suitable time period and the encapsulated, embedded and/or covalently attached pharmaceutical and/or drug is released from the particulate polymer carriers to provide a therapeutic effect. The polymer itself is also degraded in vivo to provide its own therapeutic benefits.

Antioxidant polymers as antineoplastic drug

It has been discovered that antioxidants induce cell cycle arrest, and are thus useful to enhance the efficacy of antineoplastic drugs for the treatment of abnormal cell proliferation. It has been also discovered that antioxidants not only increase the cytotoxicity of antineoplastic agents to abnormally proliferating cells, but they also decrease the toxicity of antineoplastic agents to normal cells (see, e.g., U.S. Pat. Nos. 5,035,878 and 5,294,430).

One of skill in the art will readily appreciate that polymers larger than about 40,000 Daltons accumulate selectively in the tumor site due to the enhanced permeability and retention ("EPR") effect (Maeda et al., J. CONTROLLED RELEASE 65, 271 , 2000). Therefore, the present invention also provides methods to decrease the toxicity of an antineoplastic agent administered for the treatment of abnormally proliferating cells and/or to decrease the toxicity of antineoplastic agents to normal cells. The methods may comprise administering the inventive antioxidant [1 ,2]- dithiolane derivatives, oligomers or polymers thereof prior to, with, or following the antineoplastic treatment, as well as methods for administering the inventive antioxidant [1 ,2]-dithiolane derivatives, oligomers or polymers thereof to a subject in need thereof.

One aspect of this invention relates to the syntheses of antioxidant [1 ,2]- dithiolane derivatives and uses of these compounds as monomers that are polymerized into biodegradable antioxidant polyacetals and polyesters. Another aspect of this invention relates to the syntheses of antioxidant polymers by covalent attactment of the antioxidant [1 ,2]-dithiolane derivatives to diverse functional polymers including, but not limited to, polycarboxylic acid, polysaccharides, polyamines, polyols and dendritic polymers.

Polymerization of the the antioxidant [1 ,21-dithiolane derivatives to polvacetals and polyesters

One embodiment of the present invention is directed to methods of making degradable antioxidant polyacetals and polyesters. Polyacetals are polymers that

contain recurring acetal bonds and polyesters are polymers that contain recurring ester bonds. Hydrolytically degradable polymers containing acetal bonds have been reported (Tomlinson et al., MACROMOLECUL.ES. 35:473-480, 2002).

Polyacetals and polyesters of the present invention may comprise a recurring unit; for example, represented by the following formulas:

Formula 1

Formula 2

wherein A and B are selected from the group consisting of branched and unbranched alkyl, aryl, cycloaliphatic and aralkyl group, and is saturated or unsaturated, and may optionally contain hetero atoms, and R is selected from the the antioxidant [1 ,2]-dithiolane derivatives described herein. The monomers may be polymerized via biodegradable ester bond or acetal bond, which are susceptible to hydrolytic degradation (see Figures 1A and 1 B). Upon variation of the monomers, polymers with varying hydrophobicity may be prepared. Water-soluble polymers may be used as the macromolecular antioxidant component of injectable pharmaceutical formulations. Hydrophobic polymers may be used for the preparation of antioxidant nanoparticles or microparticles that, upon administration, circulate through the body for a prolonged period of time and thus provide controlled, sustained release of the small molecular antioxidants. These antioxidants may be delivered to areas of the body including but not limited to tissue, brain, and cell.

[1,21-Dithiolane Derivatives

In the present invention, various types of monomeric [1 ,2]-dithiolane derivatives are designed for the preparation of the antioxidant polyacetals and polyesters as follows:

Type I - Structures of 1,2-dithiolane(diols) Formula 3 Formula 4 Formula 5

Formula 6 Formula 7 Formula 8

Formula 9 Formula 10

Type Il - Structures of 4-(amino)-1 ,2-dithiolane

Formula 11 Formula 12 Formula 13 Formula14

Formula 15 Formula 16 Formula 17 Formula 18

wherein Ri, R ₂ , R ₃ and R4 are each independently selected from the group consisting of a branched and unbranched alkyl, aryl, cycloaliphatic and aralkyl group, is saturated or unsaturated, and may optionally contain hetero atoms.

The monomeric [1 ,2]-dithiolane derivatives are also prepared by the conjugation of a Type I dithiolane derivative with an acryloyl chloride as follows:

Examples of the combined monomers include compounds with the following formulas.

Type III - Structures of 1 ,2-dithiolane-bis(acrylate ester) Formula 19 Formula 20

Formula 23 Formula 24

Formula 25 Formula 26

In addition to the monomeric [1 ,2]-dithiolane derivatives described above, the commercially available divinyl ether of Type I and Il and bis(acrylate ester) may be used for which one or more [1 ,2]-dithiolane derivatives may be conjugated thereon. The acetals and divinyl ether serves as the polymer backbone.

Pivinyl ether Type I

wherein the R group may be a hydrocarbon group; for example, an alkyl, aryl, cycloaliphatic or aralkyl group; and may be saturated or unsaturated. The R group may contain hetero atoms (e.g., nitrogen, oxygen, sulfur, etc.).

Divinyl ether Type Il

wherein n may be from 2 to 100.

Bis(acrylate ester)s

wherein B may be selected from the group consisting of a branched or unbranched alkyl, aryl, cycloaliphatic and aralkyl group, is saturated or unsaturated, and optionally contains hetero atoms.

Bis(acrylate ester) may be prepared using organic reactions well known to those of ordinary skill in the art as follows:

wherein R may be any of a wide variety of substituents; for example, R may be selected from the group consisting of a branched or unbranched alkyl, aryl, cycloaliphatic and aralkyl group, is saturated or unsaturated, and optionally contains hetero atoms.

Diols that are useful in the present inventive polymers include, but are not limited to commercially available one as follows:

Illustrated below are examples of divinyl ethers, which are commercially available or may be prepared using organic reactions well known to those of ordinary skill in the art. Divinyl ethers that are useful in the present inventive polymers include, but are not limited to commercially available ones as follows:

Bis(acrylate ester) that are useful in the present inventive polymers include, but are not limited to, commercially available diacrylates as follows:

EXAMPLES

The following examples are provided to better illustrate the claimed invention and are not to be interpreted as limiting the scope of the invention. To the extent that specific materials are mentioned, it is merely for purposes of illustration and is not intended to limit the invention. One skilled in the art may develop equivalent means or reactants without the exercise of inventive capacity and without departing from the scope of the invention. One skilled in the art will also readily recognize that the reaction schemes shown herein are simplified and stoichiometric proportions will be readily determined without undue experimentation. The inventive polymers may also be prepared by any method known in the art.

Example 1 Polymer-Type I

In one embodiment, the Type I dithiolane repeating units polymerize with a divinyl ether to produce polymers as follows:

Synthesis of Polymer - Representative polymerization in tetrahvdrofuran A Type I [1 ,2]-Dithiolane monomeric unit (5 mmol, 1.0 equiv) and divinyl ether

(5.2 mmol, 1.04 equiv) are mixed in tetrahydrofuran (THF) (20 mL) with molecular sieves (1.0 g, 3 A, 10-20 mesh beads, Fluka) at room temperature. The reaction mixture is stirred for 20 min and p-toluenesulfonic acid monohydrate(TSA, 0.15

mmol, 0.03 equiv) is added. The mixture mixture is stirred for two days at room temperature and aqueous NaHCO ₃ (8% w/v, 2.0 ml) is added to the reaction mixture. The organic phase is extracted with ethylacetate (3x20 ml_), dried over sodium sulfate and the volume of the solvent is reduced (~20 ml_) by rotary evaporation at room temperature. The organic solution is added dropwise into stirred hexane, the polyacetal is collected and placed into a fresh solution of hexane and stirred for an additional 10 min. The polyacetal is again collected and then dried in a vacuum at room temperature for 4 hours to give the polymer.

Examples of polymers in these embodiments include but are not limited to the following: Formula 27

Formula 28

Formula 29

Formula 30

Formula 31

wherein A is selected from the group consisting of branched or unbranched alkyl, aryl, cycloaliphatic and aralkyl group, is saturated or unsaturated, and may optionally contain hetero atoms.

In particular embodiments A is selected from the group consisting of — CH2CH2 — , — CH2CH2CH2CH2 — , — CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ — , — CH ₂ CH ₂ OCH ₂ CH ₂ -, and -CH ₂ CH ₂ OCH ₂ CH ₂ OCH ₂ CH ₂ -.

Example 2 Polymer- Type Il

In another embodiment, a Type Il dithiolane repeating unit polymerizes with a bis(acrylate ester) to produce polymers as follows:

Synthesis of Polymer -- Representative polymerization in methanol The polymer is synthesized by Michael addition of the amines to diacryl esters. In an exemplary experiment, diacrylate (40 mmol, 1 equiv) and [1 ,2]-dithiolane amine (40 mmol, 1 equiv) are dissolved in anhydrous methanol (100 ml). The reaction mixture is stirred for two days at room temperature. The reaction mixture is added dropwise into stirred hexane or diethyl ether. The polyacetal is collected and dried in a vacuum at room temperature for 4 hours to give the polymer.

Examples of the polymers in these embodiments include but are not limited to the following: Formula 32

Formula 33

Formula 34

Formula 35

wherein B is selected from the group consisting of a branched or unbranched alkyl, aryl, cycloaliphatic and aralkyl group, is saturated or unsaturated, and optionally contains hetero atoms, and R ₃ and R ₄ are selected independently from the group consisting of a branched or unbranched alkyl, aryl, cycloaliphatic and aralkyl group, is saturated or unsaturated, and optionally contains hetero atoms.

In particular embodiments, B is selected from the commercially available bis(acrylate)s. Bis(acrylate ester) that are useful in the present inventive polymers include, but are not limited to, commercially available: 1 ,2-ethanediol diacrylate, 1 ,3- propanediol diacrylate, 1 ,4-butanediol diacrylate, 1 ,6-hexanediol diacrylate, and 2,5- hexanediol diacrylate. Examples of polymers in these embodiments include, but are not limited to the following:

Formula 37

Formula 38

Formula 39

Formula 40

Formula 41

Example 3 Polymer Type III

In one embodiment, the inventive polymers are prepared by conjugation of two monomers, both of which contain dithiolane. The Type 2 dithiolane monomer contains a primary amine and the dithiolane monomer contains a bis(acrylate ester). The polymers are prepared by the conjugate addition of a primary amine to a bis(acrylate ester). The reaction scheme is shown below.

Synthesis of Polymer - Representative polymerization in methanol In an exemplary experiment, [1 ,2]-dithiolane diacrylate (40 mmol, 1 equiv) and

[1 ,2]-dithiolane amine (40 mmol, 1 equiv) are dissolved in anhydrous methanol (100 ml). The reaction mixture is stirred for two days at room temperature. The reaction mixture is added dropwise into stirred hexane or diethyl ether. The polyacetal is collected and dried in a vacuum at room temperature for 4 hours to give the polymer. Examples of polymers in these embodiments include, but are not limited to the following:

Formula 43

Formula 45

Formula 46

Formula 47

Formula 48

Formula 49

Formula 50

Formula 51

Formula 52

Formula 53

Formula 54

Formula 55

Formula 56

Formula 57

Formula 58

Formula 63

Formula 64

Formula 65

Formula 66

Formula 67

Formula 68

wherein X is selected from the group consisting of a branched or unbranched alkyl, aryl, cycloaliphatic and aralkyl group, is saturated or unsaturated, and optionally contains hetero atoms, and Ri, R ₂ , R ₃ and R ₄ and R ₅ are each independently selected from the group consisting of a branched or unbranched alkyl, aryl, cycloaliphatic and aralkyl group, is saturated or unsaturated, and optionally contains hetero atoms.

Example 4 Polymer Type-IV

In another embodiment, the inventive polymers are prepared by the addition of primary amines to a dithiolane monomer. The reaction scheme is shown below.

Synthesis of Polymer - Representative polymerization in methanol In a manner similar to that described above, [1 ,2]-dithiolane diacrylate (40 mmol, 1 equiv) and primary amine (40 mmol, 1 equiv) are dissolved in anhydrous methanol (100 ml). The reaction mixture is stirred for two days at room temperature.

The reaction mixture is added dropwise into stirred hexane or diethyl ether. The polyacetal is collected and dried in a vacuum at room temperature for 4 hours to give the polymer.

Examples of polymers in these embodiments include, but are not limited to the following:

Formula 69

Formula 70

Formula 71

Formula 72

Formula 73

wherein Ri, R ₂ , R ₄ and R ₅ are each independently selected from the group consisting of a branched or unbranched alkyl, aryl, cycloaliphatic and aralkyl group, is saturated or unsaturated, and optionally contains hetero atoms.

In alternative embodiments, R ₅ is selected from the commercially available primary amines. Examples of polymers in these embodiments include, but are not limited to the following:

Formula 74

Formula 75

Formula 76

wherein m is an integer of at least 2.

Example 5 Polymer-Type V

In another embodiment, the inventive polymers are prepared by the addition of a diamine to a dithiolane monomer. The reaction scheme is shown below.

Synthesis of Polymer - Representative polymerization in methanol In a manner similar to that described above, [1 ,2]-dithiolane diacrylate (40 mmol, 1 equiv) and diamine (40 mmol, 1 equiv) are dissolved in anhydrous methanol

(100 ml). The reaction mixture is stirred for two days at room temperature. The reaction mixture is added dropwise into stirred hexane or diethyl ether. The polyacetal is collected and dried in a vacuum at room temperature for 4 hours to give the polymer.

Examples of polymers in these embodiments include, but are not limited to the following:

Formula 77

Formula 78

Formula 79

Formula 80

Formula 81

In particular embodiments, the diamine is selected from commercially available primary amines. Examples of polymers in these embodiments include but are not limited to the following: Formula 82

Formula 83

Formula 84

Formula 85

Example 6 Polymer-Type Vl

In another embodiment, the inventive polymers are prepared by the addition of a bis(secondary amine) to a dithiolane monomer. The reaction scheme is shown below.

Synthesis of Polymer -- Representative polymerization in methanol In a manner similar to that described in above, [1 ,2]-dithiolane diacrylate (40 mmol, 1 equiv) and N,N'-dimethylethylenediamine (40 mmol, 1 equiv) are dissolved in anhydrous methanol (100 ml). The reaction mixture is stirred for two days at room temperature. The reaction mixture is added dropwise into stirred hexane or diethyl ether. The polyacetal is collected and dried in a vacuum at room temperature for 4 hours to give the polymer.

Examples of polymers in these embodiments include but are not limited to the following: Formula 86

Formula 87

Formula 88

Formula 89

Formula 90

Formula 91

Formula 92

In particular embodiments, the bis(secondary amine) is selected from commercially available primary amines. Examples of polymers in these embodiments include but are not limited to the following: Formula 93

Formula 95

Formula 96

Example 7 Polymer-Type VII

In another embodiment, the inventive polymers are prepared by the addition of a cyclic bis(secondary amine) to a dithiolane monomer. The reaction scheme is shown below.

Synthesis of Polymer -- Representative polymerization in methanol In a manner similar to that described above, [1 ,2]-dithiolane diacrylate (40 mmol, 1 equiv) and piperazine (40 mmol, 1 equiv) are dissolved in anhydrous methanol (100 ml). The reaction mixture is stirred for two days at room temperature. The reaction mixture is added dropwise into stirred hexane or diethyl ether. The polyacetal is collected and dried in a vacuum at room temperature for 4 hours to give the polymer.

Examples of polymers in these embodiments include but are not limited to: Formula 97

Formula 98

Formula 100

Preparation of the antioxidant polymers by covalent attachment of the antioxidant [1,2]-dithiolane derivatives to diverse polymers

In another aspect, the antioxidant polymers are prepared by covalent attachment of the antioxidant [1 ,2]-dithiolane derivatives to functional polymers.

The attachment of the antioxidant [1 ,2]-dithiolane derivatives to the polymers via an amide or ester bond may be performed by any appropriate method known in the art. In one embodiment, the starting polymer contains pending carboxylic acid side groups and the [1 ,2]-dithiolane derivatives are covalently bonded to the polymer via biodegradable ester or amide bond. The [1 ,2]-dithiolane derivatives include but are not limited to the following:

wherein the R ₃ and R ₄ groups may be hydrocarbon groups; for example, an alkyl, aryl, cycloaliphatic or aralkyl group; and may be saturated or unsaturated. The R ₃ and R ₄ groups may contain hetero atoms (e.g., nitrogen, oxygen, sulfur, etc.).

The starting polymers may be of natural or synthesitc origin, and homopolymers or block copolymers or dendrimers with carboxylic acid terminated dendrimers. For lipolol synthesis, Journal of Pharmaceutical Sciences, 85, 1996, 496-504 may provide guidance to one of skill in the art. For the synthesis of monohydroxy dithiolane derivatives, European Journal of Medicine Chemistry 38, 2003, 1-11 may provide guidance to one of skill in the art.

The polycarboxylic acids include, but are not limited to: Poly(α-aspartic acid)

jluta imic acid)

Poly(γ-glutamic acid)

Poly(β-malic acid acid)

Poly(α,β-malic acid)

β-type unit α-type unit Poly(acrylic acid)

Poly(alkylacrylic acid)

Poly(acrylamide-co-acrylic acid)

Poly(amido amine) (PAMAM) dendrimer, carboxylic acid terminated

Examples of the inventive antioxidant polymers include but are not limited to the following: Formula 101 Formula 102

Formula 103 Formula 104

Formula 105 Formula 106

Formula 107 Formula 108

Formula 109

In another embodiment, the starting polymer contains pending primary amine or secondary amine groups and the 1 ,2-dithiolane-3-pentanoic acid (thioctic acid, α- lipoic acid) is covalently bonded to the polymer via, amide bond. The starting polymers may be of natural or synthesitc origin, and homopolymers or block copolymers or dendrimers. The starting polyamines include, but not limited to: poly(ethyleneimine), poly(propylenimine), polylysine, chitosan, primary amine terminated dendrimers including, but not limited to, poly(amido amide)(PAMAM) dendrimers, poly(propylenimine) dendrimer, octaamine dendrimers, and hexadecaamine dendrimer.

Examples of the inventive antioxidant polymers include but are not limited to the following formulas: Formula 110 Formula 111 Formula 112

Formula 113

Formula 114

Dendrimers are hyperbranched polymers in which the atoms are arranged in many branches and subbranches along a central backbone of carbon atoms. (See e.g., Zeng, F and Zimmerman, S. C, Chem. Rev. 1997, 97, 1681-1712 Matthews et al., Prog. Polym. ScL, 23, 1-56, 1998)

In another embodiment, the starting polymer contains pending hydroxyl groups and the 1 ,2-dithiolane-3-pentanoic acid (thioctic acid, α-lipoic acid) is covalently bonded to the polymer via, ester bond. The starting polymers may be of natural or synthesitc origin, and homopolymers or block copolymers, polysaccharides including, but not limited to, pullulan, amylose, mannan, amylopectin, dextran and cyclodextrin, and hydroxyl terminated dendrimers. The polyols include, but not limited to: Polyvinyl alcohol) Polyvinyl alcohol-co-ethylene) ethylene

Pullulan Dextran

β-Cyclodextrin

n= 7

Examples of the inventive antioxidant polymers include but are not limited to the following formulas: Formula 115 Formula 116

Formula 117 Formula 118

Preparation of Various Compounds

All reactions for the synthesis of 1 ,2-dithiolane derivatives are monitored by thin layer chromatography (TLC): silicagel plates from Merck 60 F254; compounds are visualized by irritation with UV light and/or by treatment with a solution of 1.5g of KMnO ₄ , 1Og K ₂ CO ₃ , and 1.25mL 10% NaOH in 20OmL of H ₂ O, followed by gentle heating. Compounds with amine functional group are visualized by ninhydrin test.

Example 8 Preparation of 1,2-Dithiolane(diol)

α-Lipoic acid (15 mmol) and serinol (15 mmol) are dissolved in 100 mL dichloromethane, followed by the addition of 1-hydroxybenzotriazole (HOBt, 20 mmol) and TEA (30 mmol). The reaction mixture is cooled to 0 °C and 1-ethyl-3-(3-

dimethylaminopropyl) carbodiimide hydrochloride (EDC- HCI, 20 mmol) is added portionwise. The mixture is stirred for 5 h at room temperature. The reaction mixture is washed with deionized water (3x 200 ml_), dried with MgSO ₄ and the solvent is evaporated under vacuum. The crude product was purified by silicagel column chromatography (250 ml_) eluting with CHCI ₃ :MeOH (45:5).

Example 9 Preparation of 1,2-Dithiolane(diol)

Step 1 : Synthesis of lipoic acid benzylidene glycerol ester α-Lipoic acid (15 mmol) and 1 ,3-O-benzylideneglycerol (15 mmol) are dissolved in 100 ml_ dichloromethane, followed by the addition of 4-(dimethylamino) pyridine (DMAP, 20 mmol). The reaction mixture is stirred for 10 min at room temperature and EDC- HCI (20 mmol) was added portionwise. The mixture is stirred for 5 h at room temperature. The reaction mixture is washed with deionized water (3χ 200 ml_), dried with MgSO ₄ and the solvent was evaporated under vacuum. The crude product is purified by silicagel column chromatography (250 mL) eluting with CHCI ₃ :MeOH (95:1).

Step 2: Synthesis of lipoic acid glycerol ester α-Lipoic acid benzylidene glycerol ester (10 mmol) is dissolved in 20 ml of methanol containing 0.6 ml of cone. HCI and refluxed for 4 hours. 250 ml of water is

added, the pH is adjusted to 6 with solid NaOH, and methanol is evaporated under vacuum. NaCI was added to ~10% and the product is extracted with dichloromethane (3χ 100 ml_). The combined dichloromethane extracts are dried over Na ₂ SO ₄ , filtered and evaporated. The residue is dried under vacuum and the product is purified by chromatography on a silica gel column eluted with ethyl acetate.

Example 10 Preparation of 1,2-Dithiolane(diol)

Step 1 : Pentaerythritol monobenzaldehyde was synthesized according the procedure as described in the literature (See e.g., Organic Syntheses, Coll. Vol. 4, p.679; Vol. 38, p.65)

Step 2: Synthesis of bis-(methanesulfonic acid ester) of monobenzalpentaerythritol

Methanesulfonyl chloride (20.7 g, 0.18 mol) was added at 5 °C to a stirred solution of monobenzalpentaerythritol (0.028 mol) and triethylamine (56 ml) in dichloromethane (115 ml). The mixture was stirred at 5 °C for 5 h and at 20 °C for 20 h. Dichloromethane (200 ml) was added and the mixture was washed with an aqueous solution of sodium hydrogen carbonate, dried with Na ₂ SO ₄ and concentrated to dryness under vacuum. Chromatography of the residue on silicagel (1.2 L) eluting with hexane/ethyl acetate (50:50) gives bis-(methanesulfonic acid ester) of monobenzalpentaerythritol.

Step 3: Synthesis of dimercaptoacetyl of monobenzalpentaerythritol (under argon atmosphere)

Bis-(methanesulfonic acid ester) of monobenzalpentaerythritol (0.015 mol) was dissolved in dimethylformamide (50 ml). Potassium thioacetate (0.06 mol) in 50 mL of DMF was added dropwise. The reaction mixture was stirred overnight at room temperature and then concentrated under vacuum, poured into brine (300 mL) and extracted with ethyl acetate (3χ 200 mL). The organic layer was washed with water (3 ^χ 300 mL), dried over sodium sulfate and evaporated under vacuum. Chromatography of the residue on silicagel eluting with a mixture of hexane and ethyl acetate (50:50) gives 1 ,2-dithiolane of monobenzalpentaerythritol.

Step 4: Synthesis of 1 ,2-dithiolane of monobenzalpentaerythritol

A solution of dimercaptoacetyl monobenzalpentaerythritol (4.1 mmol) in EtOH (20 ml) is treated with 10 ml of aqueous 1 N NaOH at room temperature for 1 h. The mixture is diluted with CH ₂ CI ₂ (100 ml) and then an aqueous solution of 0.1 M iodine (4.5 mmol) is added dropwise. The reaction mixture was stirred for 2 hours at room temperature and 1 mmol of Na ₂ S ₂ O ₃ (1 M aqueous solution) was added to the reaction mixture. The organic phase was separated, washed with water (3( 200 mL), dried with magnesium sulfate, and evaporated at room temperature. The crude product is chromatographed on silica gel (200 mL) using a solvent mixture of hexane and ethyl acetate (40:20) as eluent to give 1 ,2-dithiolane of monobenzalpentaerythritol.

Step 5: Synthesis of 1 ,2-dithiolane pentaerythritol 1 ,2-Dithiolane of monobenzalpentaerythritol (10 mmol) was dissolved in 20 ml of methanol containing 0.6 ml of cone. HCI and refluxed for 4 hours. 250 ml of water was added, the pH was adjusted to 6 with solid NaOH, and methanol was evaporated under vacuum. NaCI was added to ~10% and the product was extracted with dichloromethane (3χ 100 mL). The combined dichloromethane extracts were dried over Na ₂ SO ₄ , filtered and evaporated. The residue was dried under vacuum and the product is purified by chromatography on a silica gel column eluted with ethyl acetate.

Example 11 Preparation of 1,2-Dithiolane(diol) of Type III

Step 1 : synthesis of Dibromomonobenzalpentaerythritol

2,2-Bis(bromomethyl)-1 ,3-propanediol (100 mmol), benzaldehyde (100 mmol), and p-toluenesulfonic acid monohydrate (3 mmol) are dissolved in 150 mL of cyclohexane. The stirred mixture is heated with azeotropic removal of water. The solution is allowed to cool to room temperature and then evaporated under vacuum at room temperature. The residue is dissolved in 100 mL of diethyl ether, and

washed with saturated aqueous potassium bicarbonate (50 ml_), and with water (2 x 50 ml_). The ether layer is dried over magnesium sulfate and filtered. The solvent is evaporated under vacuum at room temperature. The solid crude product is collected by filtration. The crude solid product is triturated with 50 ml_ of hexanes and the purified product is collected by filtration.

Step 2: Synthesis of Bis-(diethyl malonate) monobenzalpentaerythritol Sodium (100 mmol) is added over 20 min to ethanol (100 ml_) to give sodium ethoxide. Malonic acid diethyl ester (100 mmol) is added and the mixture is stirred for 10 min and concentrated under vacuum to dryness. The residue is taken up with toluene and the suspension concentrated under vacuum to dryness. The residue is dissolved in dimethylformamide (200 mL), dibromomonobenzalpentaerythritol (0.50 mmol) is added, the mixture stirred for 4 days at 20 °C and concentrated to dryness under vacuum. The residue is dissolved in ether, washed successively with aqueous solutions of sodium hydrogencarbonate and lithium chloride, dried (Na ₂ SO ₄ ) and the solvent is evaporated to dryness. The excess of diethyl malonate is distilled from the residue under reduced pressure to give bis-(diethyl malonate) monobenzalpentaerythritol.

Step 3: Synthesis of bis-(propane-1 ,3-diol) monobenzalpentaerythritol

Bis-(diethyl malonate) monobenzalpentaerythritol (100 mmol) dissolved in diethyl ether (100 mL) is added dropwise to a lithium aluminium hydride in diethyl ether (100 mL) suspension. The mixture is stirred for 2 h at reflux temperature and 20 h at 20 °C. After cooling at 5 °C, water (5 mL), 2 N aqueous solution of sodium hydroxide (10 mL) and water (5 mL) is successively added. The suspension is filtered, the solid is washed with diethylether and the combined filtrates are dried (Na ₂ SO ₄ ) and concentrated under vacuum. The crude product is chromatographed on silica gel using a solvent ethyl acetate as eluent to give the product.

Step 4 - Step 7 were performed in a manner similar to that described in the Example for preparation of 1 ,2-dithiolane pentaerythritol.

Example 12 Preparation of 1,2-Dithiolane(diol) of Type Il

The compounds are prepared in a manner similar to that described above.

Example 13

Preparation of 4-Bromo-[1 ,2]-Dithiolane (Type I) (See e.g. Morera et. al. Org. Lett. 4, 1139-1142, 2002)

Steps 1 and 2: Synthesis of 2-Benzyloxy-1 ,3-propanediol

Sodium hydride (1 g, 60 % in mineral oil, 42 mmol, 1.67 g) is suspended in freshly distilled THF (100 ml_), and the mixture is cooled in an ice/H ₂ O bath. 1 ,3-0- Benzylidene glycerol (28 mmol) is added in portions, and the mixture is stirred for 15 min. Benzyl bromide (40 mmol) is added via a syringe, and the reaction is stirred at 0 °C to room temperature overnight. Approximately half of the THF is evaporated under reduced pressure, and 20 ml_ of H ₂ O and 60 mL of 10 % aqueous HCI are added. The mixture is refluxed for 2 h, cooled to room temperature, and is poured into 10 mL of saturated aqueous Na ₂ CO ₃ . The solution is extracted with ethyl acetate (3 times with 20 mL). The extracts are dried over Na ₂ SO ₄ and evaporated and purified by column chromatography (eluantfrom hexane/ethyl acetate (50/50) ethyl acetate 100%).

Step 3: A solution of 2-Benzyloxy-1 ,3-propanediol (20 mmol) in dry CH ₂ CI ₂ (50 mL) is additioned with dry TEA (90 mmol) and then treated with methanesulfonyl chloride (65 mmol) at 0 °C for 30 min (dropwise added at 0 °C). The reaction mixture is stirred for 2 h at room temperature. The mixture is washed with 50 mM sodium bicarbonate (6-7 times with 300 mL), dried over magnesium sulfate and the solvent is evaporated under reduced pressure. The product is precipitated by adding of hexane and slowly evaporating CH ₂ CI ₂ and the yellowish product is washed with hexane and dried.

Step 4: 2-Benzyloxy-1 ,3-dimethanesulfonyl propanediol (45 mmol) is dissolved in DMF (180 mL) and sulfur (1.5 g) and sodium sulfide monohydrate (11 g) is added.

The reactionmixture is stirred at 85°C for 4 h and diethylether is added (500 mL).

The reaction mixture is washed with brine, dried with sodium sulfate and evaporated under vacuum. The crude product is purified by column chromatography

(eluant: hexane/ethyl acetate, 95/5).

Step 5: 4-(Benzyloxy)-[1 ,2] dithiolane (7.06 mmol) is dissolved in 1 ,2-dichloroethane

(20 mL). A 1 M solution of boron tribromide-methylsulphide complex in

dichloromethane (20 ml_) is added and the mixture stirred at 20 °C for 2 h, poured in an aqueous solution of sodium hydrogencarbonate and extracted with diethyl ether. The combined organic layers are dried (Na ₂ SO ₄ ) and evaporated at room temperature. The crude product is purified by column chromatography (eluant: 100% CHCI ₃ ).

Step 6: Synthesis of 4-Bromo-[1 ,2]-Dithiolane

(See e.g., Saah et al. Journal of Pharmaceutical Sciences 85,496-504, 1996)

4-Hydroxy-[1 ,2]- Dithiolane (3 mmol) and triphenylphosphine (9 mmol) are dissolved in 15 mL of anhydrous tetrahydrofuran, THF. Zinc bromide (3 mmol) in 10 mL of THF is added followed by diethyl azidodicarboxylate, DEADC (9 mmol) in 5 mL of THF. The mixture is stirred at room temperature under nitrogen atmosphere until 4- Hydroxy-[1 ,2]- Dithiolane disappears. Methanol (2.0 mL) is then added to the reaction mixture and after 5 min, the mixture is extracted with ether (20 mL), the organic layer is washed with 12 mL of water, saturated Na ₂ CO ₃ , and brine successively, and the organic solvent is evaporated under vacuum at room temperature. The crude product is purified by silicagel column chromatography (eluanthexane/ethyl acetate, 95/5).

Example 14

Preparation of α-Bromo-ω-[1 ,2]-Dithiolane from diols (Type I)

Guillonneau et al. European Journal of Medicinal Chemistry 38, 1-11 , 2003 and Morera et. al. Org. Lett. 4, 1139-1142, 2002 provides one skilled in the art guidance to prepare this particular compound.

Example 15

Preparation of [1 ,2]-dithiolane-3-pentanol(Lipolol)

[1 ,2]-dithiolane-3-pentanol(lipolol) is prepared in a manner similar to that described in the Example for preparation of 4-bromo-[1 ,2]-dithiolane.

Example 16 Preparation of 1 ,2-Dithiolane(diol)

Step 1 : Synthesis of bis-(methanesuifonic acid ester) of boc-serinol

Methanesulfonyl chloride (130 mmol) was added at 5 °C to a stirred solution of boc-serinol (40 mol) and triethylamine (25 ml) in dichloromethane (100 ml). The mixture was stirred at 5 °C for 5 h and at 20 °C for 20 h. Dichloromethane (200 ml) was added and the mixture was washed with an aqueous solution of sodium hydrogen carbonate (50 mM), dried (Na ₂ SO ₄ ) and concentrated to dryness under vacuum. Chromatography of the residue on silicagel (1.2 L) eluting with hexane/ethyl acetate (50:50) gave bis-(methanesulfonic acid ester) of boc-serinol.

Step 3: Synthesis of dimercaptoacetyl of boc-serinol Bis-(methanesulfonic acid ester) of boc-serinol(0.015 mol) was dissolved in dimethylformamide (50 ml). Potassium thioacetate (0.06 mol) in 50 ml_ of DMF was added dropwise. The reaction mixture was stirred overnight at room temperature and then concentrated under vacuum, poured into brine (300 ml_) and extracted with ethyl acetate (3χ 200 ml_). The organic layer was washed with water (3χ 300 mL), dried over sodium sulfate and evaporated under vacuum. Chromatography of the residue on silicagel eluting with a mixture of hexane and ethyl acetate (50:50) gave 1 ,2-dithiolane of boc-serinol.

Step 4 : Synthesis of 1 2-dithiolane of boc-serinol

A solution of dimercaptoacetyl boc-serinol (4.1 mmol) in EtOH (20 ml) was treated with 10 ml of aqueous 1 N NaOH at room temperature for 1 h. The mixture was diluted with CH ₂ Cl ₂ (100 ml) and then an aqueous solution of 0.1 M iodine (4.5 mmol) is added dropwise. The reaction mixture was stirred for 2 hours at room temperature and 1 mmol of Na ₂ S ₂ O ₃ (1 M aqueous solution) was added to the reaction mixture. The organic phase was separated, washed with water (3χ 200 ml_), dried with magnesium sulfate, and evaporated at room temperature. The crude product was chromatographed on silica gel (200 ml_) using a solvent mixture of hexane and ethyl acetate (40:20) as eluent to give 1 ,2-dithiolane of boc-serinol.

Step 5: Synthesis of 1 ,2-dithiolane serionol

1 ,2-Dithiolane of boc-serinol (1 mmol) was dissolved in 2.5 ml of dichloromethane and 2.5 mL of TFA was added at 0 °C. The reaction mixture was stirred for 30 min at 0 °C and evaporated under vacuum. The remaining TFA was removed azotropically with ether and tolune and dried under high vacuum at room temperature. The crude product was purified by chromatography on a silica gel column eluted with CHCI ₃ :MeOH (45:5).

Example 17 Preparation of α- Amino- ω-[1, 2]-dithiolan-4-yl-alkane

Step 1 : Sodium (11 g, 0.48 mol) is added over 20 min to ethanol (400 ml_) to give sodium ethoxide. Malonic acid diethyl ester (80 g, 0.5 mol) is added and the mixture is stirred for 10 min and concentrated under vacuum to dryness. The residue is taken up with toluene and the suspension concentrated under vacuum to dryness. The residue is dissolved in dimethylformamide (1 L), (boc-amino)alkyl bromide (0.48 mol) is added, the mixture is stirred for 4 days at 20 °C and concentrated to dryness under vacuum. The residue is dissolved in ether, washed successively with aqueous solutions of sodium hydrogencarbonate and lithium chloride, dried (Na ₂ SO ₄ ), concentrated and distilled under reduced pressure. The crude product is then purified by silicagel column chromatography.

Step 3: Synthesis of bis-(propane-1 ,3-diol) monobenzalpentaerythritol Bis-(diethyl malonate) (100 mmol) dissolved in diethyl ether (100 ml.) is added dropwise to a lithium aluminium hydride in diethyl ether (100 ml_) suspension. The mixture is stirred for 2 h at reflux temperature and 20 h at 20 °C. After cooling at 5 °C, water (5 mL), 2 N aqueous solution of sodium hydroxide (10 ml_) and water (5 ml_) is successively added. The suspension is filtered, the solid is washed with diethylether and the combined filtrates are dried (Na ₂ SO ₄ ) and concentrated under vacuum. The crude product is chromatographed on silica gel using a solvent ethyl acetate as eluent to give the product.

Step 4 - Step 6 are performed in a manner similar to that described in the Example for preparation of 1 ,2-dithiolane serinol.

Example 18

Preparation of Diamino-N,N-di[4-(1 ,2-dithiolane)] alkane from 4-bromo-[1 ,2]-dithiolane

To a solution of mono-boc-diamino alkane (5 mmol) in acetonitrile (20 ml), 4-bromo- [1 ,2]-dithiolane (10 mmol) is added at room temperature. The mixture is warmed to 50 °C, stirred for 2 h, and further stirred for 2 days at room temperature, and then poured into water. After extraction with CH ₂ CI ₂ , the organic extracts are dried over Na ₂ SO ₄ . The solvent is evaporated and the crude product is purified by column chromatography on silica gel (eluant: ethyl acetate). The deprotection and purification of the product are performed in a manner similar to that described in the Example for preparation of 1 ,2-dithiolane serionol.

Example 19 Preparation of diamino-N,N-di[(1 ,2-dithiolane)] pentyl from 4-bromo-[1 ,2J-dithiolane

The preparation is performed in a manner similar to that described above.

Example 20 Preparation of a 1 ,2-Dithiolane

To a solution of serinol (5 mmol) in acetonitrile (20 ml), 4-bromo-[1 ,2]-dithiolane (10 mmol) is added at room temperature. The mixture is warmed to 50 °C, stirred for 2 h, and further stirred for 2 days at room temperature, and then poured into water. After extraction with CH ₂ CI ₂ , the organic extracts are dried over Na ₂ SO ₄ . The solvent is evaporated and the crude product is purified by column chromatography on silica gel (eluant: ethyl acetate).

Example 21 Preparation of a 1 ,2-Dithiolane

The compound is prepared in a manner similar to that described above.

Example 22 Preparation of a 1 ,2-Dithiolane

The compound is prepared in a manner similar to that described above.

Example 23 Preparation of 1 ,2-Dithiolane(bis-acrylatel)

To a solution of Lipoic acid/Serinol (3.6 mmol) in 15 ml_ of anhydrous CH ₂ CI ₂ potassium carbonate (18 mmol) is added, and the mixture is cooled to 0 °C.

Subsequently, acryloyl chloride (18 mmol) is added dropwise within 15 min. After the mixture is stirred for 1 h at 0 °C and 48 h at room temperature, the reaction mixture is

washed with deionized water (3χ 50 ml_), dried with MgSO ₄ and the volume is reduced under vacuum (5 ml_). The crude product is purified by silicagel column chromatography (100 ml_) eluting with CHCI ₃ :MeOH (95:1).

Example 24 Synthesis of Polymer

The inventive polymers may be prepared by any method known in the art. Preferably the polymers are prepared from commercially available starting materials. In another embodiment, the polymers are prepared from easily and/or inexpensively prepared starting materials.

The synthesized polymer may be purified by any technique known in the art including precipitation, crystallization, chromatography, etc.

Example 25

Preparation of the particles

The inventive nano- and microparticles may be prepared using any method known in the art including spray drying, single and double emulsion solvent evaporation, solvent extraction, and other methods well known to those of ordinary skill in the art.

The surface charge of particles prepared with the inventive polymers may be controlled by the amount of the tertiary amine containing segment.

PH pH < 7.4 6.5

The interaction of the positively charged particles with the endolysosomal membrane may be enhanced resulting in membrane disrupture and release of the particles into the cytoplasm.

The oxidation of the dithiolane sulfer atoms to thiosulfinate will make the dithiolane containing polymers less hydrophobic, thus making them more water soluble, leading to the destabilization of the particles. The loaded drugs/therapeutics will be then released in a controlled manner in the environment of oxidative stress.

A

Various embodiments of the invention are described above in the Detailed Description. While these descriptions directly describe the above embodiments, it is understood that those skilled in the art may conceive modifications and/or variations to the specific embodiments shown and described herein. Any such modifications or variations that fall within the purview of this description are intended to be included therein as well. Unless specifically noted, it is the intention of the inventors that the words and phrases in the specification and claims be given the ordinary and accustomed meanings to those of ordinary skill in the applicable art(s).

The foregoing description of various embodiments of the invention known to the applicant at this time of filing the application has been presented and is intended for the purposes of illustration and description. The present description is not intended to be exhaustive nor limit the invention to the precise form disclosed and many modifications and variations are possible in the light of the above teachings. The embodiments described serve to explain the principles of the invention and its practical application and to enable others skilled in the art to utilize the invention in various embodiments and with various modifications as are suited to the particular use contemplated. Therefore, it is intended that the invention not be limited to the particular embodiments disclosed for carrying out the invention.

While particular embodiments of the present invention have been shown and described, it will be obvious to those skilled in the art that, based upon the teachings herein, changes and modifications may be made without departing from this invention and its broader aspects and, therefore, the appended claims are to encompass within their scope all such changes and modifications as are within the true spirit and scope of this invention. It will be understood by those within the art that, in general, terms used herein are generally intended as "open" terms (e.g., the term "including" should be interpreted as "including but not limited to," the term "having" should be interpreted as "having at least," the term "includes" should be interpreted as "includes but is not limited to," etc.).