WO2002024210A2

WO2002024210A2 - Halogen compounds for use in medicine

Info

Publication number: WO2002024210A2
Application number: PCT/GB2001/004164
Authority: WO
Inventors: Robert Edward Chapman; Robert Peter Chapman
Original assignee: Robert Edward Chapman; Robert Peter Chapman
Priority date: 2000-09-19
Filing date: 2001-09-19
Publication date: 2002-03-28
Also published as: AU2001287884A1; GB0022922D0; WO2002024210A3; EP1408993A2

Abstract

A compound for use as an active pharmaceutical substance comprising a halogen compound.

Description

DESCRIPTION

COMPOUNDS FOR USE IN MEDICINE

The present invention relates to a compound for use in medicine, more

particularly it relates to a compound for use as an active pharmaceutical substance

and the use of a compound for the manufacture of a medicament for the treatment of

cancers and other conditions where the use of an antioxidant or oxidising agents leads

to an improvement in the condition. Such conditions include, but are not limited to,

lung cancer, testicular tumours, leukemias, sarcomas lymphomas and conditions

caused by pathogens such as bacteria. Oxidative killing is important in the killing of

organisms, in particular those associated with bacterial infections such as

staphylococci which are commonly responsible for surgical infections. Oxidative

killing consumes and requires molecular oxygen which it converts to superoxide

anion. In this process a membrane bound NADPH oxidase is activated and a burst

of respiration follows. Part of the consumed oxygen is converted to a series of

oxygen radicals including superoxide, hydroxyl radical and hypocholoride which are

released into phagosomes and assist in bacterial killing. The act of oxidizing or state

of being oxidised chemically consists in the increase of positive charges in an atom

or the loss of negative charges. Most biological oxidations are accomplished by the

removal of a pair of hydrogen atoms (dehydrogenation) from a molecule. Such

oxidation must be accompanied by reduction from an acceptor molecule.

In most Western countries cancer is the second most prevalent cause of death

after heart disease and accounts for 20-25% of all deaths. Whilst in most cases the causes of cancer remain unknown, rapid advances

in the last few decades in understanding the difference between cancer cells and

normal cells at the genetic level has resulted in the widely accepted understanding

that cancer results from acquired changes in the genetic make-up of a particular cell

or group of cells which give rise to a failure of the normal mechanism regulating their

growth.

Cancer is what happens when a group of cells grows uncontrollably and in an

abnormal and disorderly way. It is really a result of what happens when the normal

growth mechanism fail for reasons that we only partly understand. Cancer cells have

two properties that make them dangerous. Then can invade into neighbouring tissues

and they can spread to distant areas of the body, forming secondary tumours of

metastases.

Cigarettes for example cause 95% of cancer of the lung as well as being a

major factor in cancers of the bladder, pancreas, mouth, oesphagas and kidney.

Cancer cells can multiply to produce literally billions of cells before a tumour

becomes big enough to detect.

Other environmental factors known to give rise to cancer, such as radiation,

chemicals, such as asbestos, and free radicals, do so by increasing the overall rate of

acquired genetic damage.

Free radical mediated damage is another cause of endogenous genetic

toxicity. Free radicals are highly reactive atoms or molecular which are produced by

normal oxidative metabolism during a variety of pathological processes, including inflammation, tissue reperfusion after vascular blockage and damage by UN light and

ionising radiation.

Free radicals can damage proteins, lipids, DΝA and other molecules by

oxidation. Individual free radicals vary considerably in their reactivity and half life

in biological systems. The hydroxyl radical is the most reactive, degrading any

molecule within diffusion distance and is considered to be the ultimate radical species

responsible for DΝA damage.

Thymine oxidation products have been detected in human urine and appear

to result from the removal of oxidised DΝA bases during DΝA repair. It has been

estimated that each human cell undergoes between 10³ and 10⁴ oxidative

modifications to the Thymine in its DΝA each day. There is evidence to suggest that

this oxidative damage is involved in some of the events of cancer induction and progress.

Lipid peroxidation occurs when a reactive radical (such as ΝO₂, OH, or

CC1, O₂ ) abstracts an atom of hydrogen from polyunsaturated fatty-acid side-

chain in membrane or lipoprotein. This leaves unpaired electron on carbon

(hydrogen atom has only one electron, so its removal must leave spare electron):

Carbon radical reacts with oxygen:

O,

♦ o_ _^ -j: Resulting peroxyl radical attacks adjacent fatty-acid side-chain to

generate new carbon radical:

U/'ό /'sfoxiO

And chain reaction continues:

Overall, attack of one reactive free radical can oxidise multiple fatty-acid

side-chains to lipid peroxides, damaging membrane proteins, making the

membrane leaky, and eventually causing complete membrane breakdown.

Despite all antioxidants some free radicals still escape to subsequently do

damage. Thus DNA undergoes constant -"oxidative damage" and has to be

repaired. Free radical-damaged proteins are degraded and the end products of

Lipid peroxidation (eg the isoprostanes) and of free radical attack on urate are

present in vivo.

Because antioxidant defences are not completely efficient increased free-

radical formation in the body is likely to increase damage.

The term "oxidative stress" is often used to refer to this effect. If

oxidative stress occurs tissues often respond by making extra antioxidant

defences. However severe oxidative stress can cause cell injury and death.

Many cancers can be cured by surgical removal if they are detected early

enough, before there has been spread of significant numbers of tumour cells to other parts of the body, and if they are readily accessible.

If complete surgical removal of the tumour is not possible, then partial

removal by surgery and/or radiotherapy or chemotherapy is usually employed.

Certain tumours are highly sensitive to chemotherapy and may be cured by the use

of chemotherapeutic drugs alone.

Numerous methods have been used to try to cure and/or treat cancer, for

example, the use of hydrazine sulphate or intravenous injection of large amounts of

vitamin C as antioxidants.

Although higher dietary intakes of antioxidant nutrients β carotene, vitamin

C and vitamin E are associated with a lower risk of cancers, including oesophageal

cancer, in case control studies the results from intervention trials have not

demonstrated any effect on either the prevalence or pre-cancerous lesions or on the

incidence and mortality of cancers such as oesophageal cancer. It is possible that the

apparent effect observed in epidemiological studies is due to confounding by other

factors for example smoking. Consequently, evidence to suggest that vitamins A, C,

E or Beta Carotene protect against the development of cancers is inconclusive.

Higher intakes of the antioxidant vitamins A, C, E and β carotene have been

variously associated with lower risks of breast, colrectal, lung, gastric and cervical

cancer in case control and prospective studies.

Most of the intervention trials that have been caused to have been carried out

so far with supplements of these vitamins have failed to confirm a hypothesised

protective effect of these vitamins on cancer. In accordance with a first aspect of the present invention there is provided a

compound for use as an active pharmaceutical substance comprising a halogen

compound.

The halogen compound may comprise at least one atom selected from the

group comprising F, Cl, Br and I. Fluorine is the most reactive (the best oxidising

agent) and Iodine the least.

Preferably, the compound comprises at least one I, Cl or Br atom. More

preferably, the compound comprises at least one I or Br atom. More preferably still,

the compound comprises at least one I atom, since I enters organic molecules more

readily than F, Br or Cl by direct addition at double bonds and by displacement of

hydrogen.

Preferably the compound comprises at least two halogen atoms. More

preferably the halogen compound is obtained by the direct combination of at least

two halogens.

The halogen compound may be solid or liquid.

The halogen compound may be any one selected from the group IC1, IBr,

ICl₃, IF₇, IF₅ or BrF₃.

Preferably the compound is IC1.

Positively charged iodine can be produced, for example, using iodine

monochloride and reducing this compound by the addition of potassium iodide in a

mixture of acetic acid and carbon tetrachloride (WIJS reagent, British Standard

BS684 section 2.13..1981 ISO 3961 - 1979 para 6.6). The positively charged iodine liberated can then saturate double bonds in the molecules of the body requiring

treatment and function as an antioxidant (Iodine Value AOCS Official Method Col

1-25, 1993) . Furthermore, positively charged Bromine and Fluorine can be

produced by a similar method

The compounds may be administered orally, intravenously, subcutaneously

or by any other route. For oral application, the compounds can be administered in

such oral dosage forms as tablets, capsules (each of which includes sustained release

ore timed release formulations), pills, powders, granules, elixirs, tinctures,

suspensions, syrups and emulsions.

The dosage requirement utilising the compounds is selected in accordance

with a variety of factors including type, species, age, weight, sex and medical

condition of the patient; the severity of the condition to be treated; the route of

administration; and the particular compound employed. An ordinarily skilled

physician or veterinarian can readily determine and prescribe the effective amount

of the compound required to prevent, counter or arrest the progress of the condition.

The adult dosage may, for intravenous application, range from 1050 mg to

1400 mg weekly.

The preferred weekly dose is from 15 to 20 mg per Kg of body weight. Thus

for a 70Kg adult, the weekly dose can range from 1050 mg to 1400 mg. This weekly

dose may be administered in divided doses from 1 to 7 times a week giving unit

doses for an adult of from 150 to 1400 mg.

The compounds can form the active ingredient, and are typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers suitably

selected with respect to the intended form of administration.

The compounds may be administered with a reducing agent. Preferably, the

reducing agent comprises an electropositive metal, such as sodium. More preferably

the reducing agent is hydrazine sulphate.

The compounds may be administered by any means that treat and/or prevent

conditions where an antioxidant or an oxidising agent are effective in treating or

preventing the condition. Such conditions include cancers and bacterial infections.

Compounds of the present invention may be useful for treating and/or

preventing conditions prevalent in humans and animals. In particular, the

compounds may be usefule for treating and/or preventing MRSA, Parkinson's

disease, Alzheimer's disease, Hodgkin's disease, BSE (Bovine Spongiform Encelphalophathy), C D (Creutzfeldt-Jakob disease), Foot and mouth disease,

AIDS, Multiple Sclerosis, heart conditions, atheroscleorsis, colitis, malaria, all

sexually transmitted diseases, including gonorrhoea and syphilis, herpes,

sclerosis, all kinds of skin conditions and may be used in all kinds of sexual

stimulants and aphrodisiacs and for impotence, and other conditions and

diseases.

In accordance with a second aspect of the present invention, there is provided

the use of a halogen compound for the manufacture of a medicament for the

treatment of cancers.

The invention will be further described, by way of example only, with reference to the following compositions.

Brominated vegetable oil.

The food additive brominated vegetable oil may be safely used in

accordance with the following prescribed conditions:

(a) The additive compiles with specifications prescribed in the Food Chemicals

Codex 3d Ed, (1981), pp. 40-41, except that free fatty acids (as oelic ) shall not

exceed 2.5 percent and Iodine value shall not exceed 16. Copies of the material

incorporated by reference may be obtained from the National Academy Press,

2101 Constitution Av, NW, Washington, DC 20418, or may be examined at the

Office of the Federation Register, 800 North Capital Street, NW Suite 700,

Washington DC 20418.

(b) The additive is used on an interim basis as a stabilizer for flavouring oil

used in fruit-flavoured beverages for which any applicable standards of identity

do not preclude such use, in an amount not to exceed 16 parts per million in the

finished beverage, pending the outcome of additional toxicological studies on

which periodic reports at 6 month intervals are to be furnished and final results

submitted to the Food and Drug Administration promptly after completion of

the studies.

Halogenation of unsaturated oils generally leads to agents which have

low toxicity. This is further illustrated by Brominated oil. Brominated oil has

been used as a clouding agent in fruit drinks. It is produced by bromination of

unsaturated oils and its yellow colour, bland taste, and neutral buoyancy are used to enhance the appearance of fruit juices including orange juice, (see

above).

Brominated oils can be obtained from Dominion Products Incorporated,

882 3rd Avenue, Brooklyn New York, USA; or

Penta Manufacturing Co, 50 Okner Parkway, Livingston, New Jersey,

USA.

Iodised Oil

Iodised oil is the subject of a monograph in the 1998 British

Pharmacopoeia and USP23. Iodised oil (also known as ethiodised oil) is an

addition product of the ethyl esters of the unsaturated fatty acids and may be

obtained from poppy seed oil obtained from A and E CONNOCK. (Perfumery

and Cosmetics Ltd), Alderholt Mill House, Fordingbridge, Hampshire, SP6 IPU

UK. It contains 35-39% of combined iodine. Iodised oil may be given by

injection. Other unsaturated oils include sunflower oil, olive oil, palm oil, soya

bean oil, rape oil maize oil, flax seed oil and the like. Unsaturated chemicals

include the fatty acids such as stearic acid and oleic acid.

Potassium Iodide is the subject of a monograph in the British

Pharmacopoeia and also in other European and American Pharmacopoeias.

An aqueus iodine solution can be made as follows. 5 grams of iodine are

added to 100 ml of water. Added to this is 10% of Potassium Iodide to make

the iodine dissolve. A desired dosage of this preparation as disclosed

hereinabove can be given 3 times a day for a short time. Substituting Fluorine in some compounds and the consequences can be

dramatic and important. Vinegar, CH₃ COOH, for example having a Fluorine

atom inserted CH₂ FCOOH, gives rise to one of only a handful of fluorine

containing compounds found in nature.

Selectively fluorinated products including F and CF₃ substituents can

improve lipophilicity and suppress metabolic detoxification processes.

Very important antibacterial agents based on 6 fluoroquinolines and

linezolid represent a new class of antibiotics.

Selective fluorinated molecules can enter biological systems. A single

fluorine atom or a trifluoromethyl group can be attached to an aromatic ring

within an active molecule. The presence of even a single fluorine atom in a

molecule can totally change the outcome of what on paper appears to be a

simple chemical transformation.

Examples of Fluorine compounds are Sodium Monofluorophosphate

0.75% w/w and sodium fluoride 0.01% w/w (Total fluoride 1050 ppm)

Halogens can be included in soap perfumes and cosmetics to benefit the

preparation as follows,

(eg) (1) A Sun burn cream

Nonionic emulsifier 100

Sunscreen agent 50

Mineral oil (cosmetic quality) 30

Cetyl alcohol 20 (2) A pearly vanishing cream

Stearic acid 200

Curd soap 50

water 800

(3) A perfume (medicated and Antiseptic)

50 Thyme oil 80 Rosemary oil

100 Cassia oil 200 lavender oil

100 clove oil 200 lemon oil

50 Eucalyptus oil

200 Rose geranium oil

20 Vetivert oil

Total 1000

Cosmetics are made by the catalytic action of hydrogen with such oils as castor,

Palm Kernel, Cotton seed, sesame coconut, Soya bean, ground nut and fish oils.

(4) Soap.

100 Benzyl acetate

150 Rosewood

50 Ceraniol Java

200 Cedarwood

50 Cananga

50 Benzyl iso-eugenol

300 Ionoue 30 Musk xylene

70 Santol

Total 1000

(5) Halogen compositions as described hereinabove can be included in food

preparations such as butter and margarine and biscuits. Hydrogenated oils are widely used in their manufacture.

Claims

1. A compound for use as an active pharmaceutical substance

comprising a halogen compound.

2. A compound as claimed in claim 1 comprising at least one atom

selected from the group comprising F, Cl, Br and I.

3. A compound as claimed in claim 2 wherein the compound comprises

at least one atom of I or Br.

4. A compound as claimed in claim 3 wherein the compound comprises

at least one I atom.

5. A compound as claimed in any one of the preceding claims comprising

two halogen atoms.

6. A compound as claimed in claim 5 wherein the compound is selected

from the group comprising ICL, IBr, IC1₃, IF₇, IF₅, BrF₃.

7. A compound as claimed in any one of claims 1 to 5 wherein the

halogen compound is potassium iodide or potassium bromide.

8. A compound as claimed in any one of the previous claims wherein the

compound is in admixture with a suitable pharmaceutical diluent, excipient or

carrier.

9. A compound as claimed in claim 8 wherein the compound is in

admixture with an unsaturated oil, fat or chemical.

10. A compound as claimed in claim 9 wherein the compound is in

admixture with an unsaturated vegetable oil or mixed unsaturated vegetable oil.

11. A compound as claimed in claim 9 or 10 comprising brominated oil

and/or iodised oil.

12. A compound as claimed in any one of the previous claims wherein

the compound is an oxidising agent or an antioxidant.

13. A compound as claimed in any previous claim for use in the

prevention of lipid peroxidation.

14. A compound as claimed in any one of the previous claims for use in

the manufacture of food preparations selected from the group comprising

butter, margarines and biscuits.

15. A compound as claimed in any one of claims 1 to 13 for use in the

treatment of cancer.

16. A compound as claimed in any one of the previous claims wherein

the compound is for use in cosmetics, soaps or perfumes.

17. A compound for use as an active pharmaceutical substance

comprising a halogen.

18. A compound as claimed in any one of the previous claims for use in

the manufacture of a medicament for treating cancer.

19. A compound as claimed in any one of the previous claims wherein

fluorine is present in a compound including the group CF, CF₂ or CF₃.

20. A compound as claimed in any previous claim wherein the halogen compound is a bacteriocide or an antibiotic.

21. A compound as claimed in any previous claim for use in any kind of chemotheropy.