Organic compounds -- part of the class 532-570 series – Organic compounds – Cyclohexadiene having atoms double bonded directly at the 1-...
Reexamination Certificate
2001-04-19
2004-02-03
Pryor, Alton N. (Department: 1616)
Organic compounds -- part of the class 532-570 series
Organic compounds
Cyclohexadiene having atoms double bonded directly at the 1-...
Reexamination Certificate
active
06686485
ABSTRACT:
BACKGROUND OF THE INVENTION
The invention relates to an improved process for the stereospecific synthesis of Coenzyme Q10, ubiquinone. The present invention also relates to the therapeutically useful optically pure isomers of Coenzyme 10 and refers to new pharmaceutical compositions which contain the optically pure isomers of coenzyme Q10 dissolved or suspended in a suitable vehicle which are useful for example in preventing anoxic tissular damage, particularly in the myocardium. Previous procedures for ubiquinone isolation had several drawbacks; many steps were involved, the yields were low, the intermediates were difficult to purify, overall costs were high, and the final products were obtained as mixtures of isomers, cis(Z) and trans(E).
Coenzyme Q gives reference to a series of quinones which are widely distributed in animals, plants and microorganisms. These quinones have been shown to function in biological electron transport systems which are responsible for energy conversion within living cells. In structure, the coenzyme Q group closely resembles the members of the vitamin K group and the tocopherylquinones, which are derived from tocopherols (vitamin E), in that they all possess a quinone ring attached to a long hydrocarbon tail. The quinones of the coenzyme Q series which are found in various biological species differ only slightly in chemical structure and form a group of related, 2-3-dimethoxy-5-methyl-benzoquinones with a polyisoprenoid side chain in the 6-position which varies in length from 30 to 50 carbon atoms. Since each isoprenoid unit in the chain contains five carbon atoms, the number of isoprenoid units in the side chain varies from 6 to 10. The different numbers of the groups have been designated by a subscript following the Q to denote the number of isoprenoid units in the side chain, as in Q10. Difference in properties are due to the difference in length of the side chain. The members of the group known to occur naturally are Q6 through Q10. Coenzyme Q functions as an agent for carrying out oxidation and reduction within cells. Its primary site of function is in the terminal electron transport system where it acts as an electron or hydrogen carrier between the flavoproteins (which catalyze the oxidation of succinate and reduced pyridine nucleotides) and the cytochromes. This process, is carried out in the mitochondria of cells of higher organisms. Certain bacteria and lower organisms do not contain any coenzyme Q. It has been shown that many of these organisms contain vitamin K, instead and that this quinone functions in electron transport in much the same way as coenzyme Q. Similarly, plant chloroplasts do not contain coenzyme Q, but do contain plastoquinones, which are structurally related to coenzyme Q. Plastoquinone functions in the electron transport process involved in photosynthesis. In some organisms, coenzyme Q is present together with other quinones, such as vitamin K, tocopherylquinones, and plastoquinones; and each type of quinone can carry out different parts of the electron transport functions.
Coenzyme Q10, is a ubiquinone. Ubiquinones are a class of lipid soluble benzoquinones that are involved in mitochondrial electron transport and are essential electron and proton carriers that function in the production of biochemical energy in all cells of aerobic organisms; participating in the transport of electrons from organic substrates to oxygen in the respiratory chain of mitochondria. In addition, coenzyme Q10 has antioxidant and membrane stabilizing properties that serve to prevent cellular damage resulting from normal metabolic processes. It plays an important role as an antioxidant to neutralize potentially damaging free radicals created in part by the energy-generating process. As an energy carrier, coenzyme Q10 is continually going through an oxidation reduction cycle. As each coenzyme Q10 molecule accepts electrons, it is reduced, when it gives up electrons, it becomes oxidized again. In coenzyme Q10's reduced form (ubiquinol), the coenzyme Q 10 molecule holds electrons loosely and will quite easily give up one or two electrons to neutralize free radicals. In its electron rich reduced form, coenzyme Q10 is as potent an antioxidant as vitamin E. Coenzyme Q10's main role as an antioxidant is in the mitochondria where it first participates in the process by which free radicals are generated and then helps to quench the extra free radicals that threaten cellular components such as DNA, RNA, and cell membranes. One of coenzyme Q10's key antioxidant actions is within the cell membrane, where it counters the oxidative attack of polyunsaturated lipids (lipid peroxidation), which causes damage in a self-propagating, destructive chain reaction that ultimately results in membrane degeneration leading to cell death.
In mammalian tissue the quinone ring of coenzyme Q10 is synthesized from the amino acids, tyrosine and phenylalanine and the polyprenyl side chain is synthesized from acetyl-CoA. The number of isoprene units depends on the species, the most common form in mammals contains ten isoprene units. Coenzyme Q10 participates in the transport of electrons from organic substrates to oxygen in the respiratory chain of the mitochondria. During this process ubiquinone is reduced to a free radical semiquinone by the uptake of a single electron. Reduction of this enzyme-bound intermediate by a second electron yields ubiquinol. This a reversible reducible process.
Ubiquinone has a characteristic light absorption band at 270 to 290 nm, which disappears when it is reduced to its quinol form; this spectral change is used to measure oxidation and reduction of ubiquinone.
The structure of coenzyme Q10 consists of a quinone ring attached to an isoprene side chain. It contains 82.08% carbon, 10.51% hydrogen and 7.41% oxygen. Its has a molecular weight of 863.37 and a formula of C
59
H
90
O
4
. The oxidized, intermediate and reduced forms of coenzyme Q10 are shown in the following drawings:
Coenzyme Q10 is used extensively as a nutritional supplement as well as a pharmacological active agent. It has wide use and acceptance in the treatment of cardiovascular disease in traditional as well as alternative medicine. It is used successfully in treating ischemic heart disease, chronic heart failure, toxin induced cardiomyopathy, hypertension and hyperlipidemia. Endogenous coenzyme Q10 functions as an essential cofactor in many metabolic pathways. Its action as an additional pharmacological agent in treatment of such cardiovascular disease processes may be to improve function of the involved tissues that are ischemic or pathologicaily altered by providing an increased energy source, by acting as a free radical scavenger and/or membrane stabilizer. In addition, coenzyme Q10 is found in high concentrations in healthy hearts and at low levels in people with congestive failure leading to the suggestion that supplementation with the coenzyme would be of help in the treatment of heart disease. It is theorized that Coenzyme Q10 might work in the heart in two ways; as an antioxidant to help thwart damage from free radicals that contribute to arterial blockage, and to help boost heart muscle action by improving energy efficiency. Additionally coenzyme Q10 may boost the effects of vitamin E, also a potent antioxidant with some potential beneficial heart effects.
Coenzyme Q10 has been used in the treatment of slow muscle degeneration (dystrophy or atrophy) and the accompanying cardiac complications typically found in these patients
In addition to its helper role in the release of energy, Coenzyme Q10 serves as an antioxidant, neutralizing free radicals that cause potentially irreversible damage to cells, tissues, and organs. Coenzyme Q10 is also believed to strengthen the immune system, so as to provide antibacterial and antiviral activity (including HIV), to increase antibody production and to induce the immune system to produce a greater number of immune acting cells. Among the increasing number of pharmacological uses ascribed to coenzyme Q10 are anticanc
Pryor Alton N.
Sommer Evelyn M.
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